Mitochondrial biogenesis is the process by which mitochondria increase in number and size. A constant renewal of mitochondria is central to maintaining the number of healthy mitochondria.

One of the important mitochondrial biogenesis factors is peroxisome proliferator-activated receptor gamma coactivator 1 PGC-1 , a transcriptional coactivator that controls specific transcription action factors, sequentially, coordinating the expression of key nuclear-encoded mitochondrial genes that are required for the proper functioning of the organelle.

PGC-1α and estrogen-related receptor-α ERRα together stimulate the function of Mfn2 to facilitate the fusion process Soriano et al. Repression of PGC-1α and Mfn2 causes a decrease in oxygen consumption, glucose oxidation, and ΔΨm, and an increase in the expression of oxidative phosphorylation proteins Chen et al.

Besides PGC-1α, other members of the PGC-1 family of coactivators, namely PGC-1β and PGC-related coactivator PRC , are also implicated in modulating mitochondrial function, but their exact role is not well understood Scarpulla, The capacity of mitochondrial biogenesis declines with aging and in neurodegenerative disease.

Notably, decreased levels of PGC-1α and Mfn2 have been reported in AD Qin et al. The activity of PGC-1α can be modulated by posttranslational signalings such as AMP-activated kinase AMPK , Akt, p38 MAPK, and the sirtuin 1 Sirt1.

Direct phosphorylation by AMPK activates PGC-1α and promotes PGC-1α dependent induction at the PGC-1α promoter Canto and Auwerx, Moreover, activation of Sirt1 through caloric restriction induces PGC-1α activity and enhances mitochondrial function Planavila et al.

Importantly, impaired AMPK, Sirt1, and PGC-1α signaling have been implicated in AD pathology, drugs that activate this signaling would provide hope in alleviating AD. The proper distribution of mitochondria throughout the cell is achieved by the mitochondrial transport mechanism.

Mitochondrial transport relies on proteins that exist in the membranes of mitochondria and transport molecules and other factors such as ions into or out of the organelles Hansen and Herrmann, ; Ruprecht et al. Mitochondrial transport mainly depends on the actin cytoskeleton in budding yeast Fehrenbacher et al.

These transport mechanisms can ensure the proper inheritance and recruitment of mitochondria. Studies with the membrane-potential indicator dye JC-1 indicate that mitochondria with high ΔΨm favorably travel to the anterograde direction, whereas mitochondria with low ΔΨm move in the retrograde direction Miller and Sheetz, These migration patterns suggest that active mitochondria are recruited to distal regions with high energy requirements, whereas impaired mitochondria are returned to the cell soma, perhaps for destruction or repair.

Multiple kinesin family members and cytoplasmic dynein have been implicated in anterograde and retrograde mitochondrial transport, respectively Hollenbeck and Saxton, Impaired mitochondrial axonal transport contributes to several human neurodegenerative conditions, including spastic paraplegia, Charcot—Marie—Tooth, ALS, HD, PD, and AD Charrin et al.

In AD, impairment of mitochondrial axonal transport precedes the accumulation of toxic protein aggregates which is linked to disturbed axonal integrity and synaptic function Stokin et al.

Mitophagy, a selective type of autophagy, is a crucial pathway for mitochondrial quality control where faulty mitochondria are sequestrated into autophagosomes for subsequent lysosomal degradation Youle and Narendra, ; Kerr et al.

Mitophagy dysfunction has been implicated in aging and multiple neurodegenerative diseases, such as AD, PD, ALS, and HD Chu, ; Cai and Jeong, In this section, we offer a detailed and timely description of the molecular mechanisms of mitophagy and discuss current therapeutic approaches that target mitophagy and improve mitochondrial function in AD.

In studies of yeast, worms Caenorhabditis elegans , fruit flies Drosophila melanogaster , zebrafish Danio rerio , and mammals such as human Homo sapiens , the molecular machinery that mediates the targeting of mitochondria to lysosomes has been elucidated Lazarou et al.

Importantly, PTEN-induced putative kinase protein 1 PINK1 -parkin-mediated mitophagy is the most widely studied mitophagy pathway Gautier et al. When mitochondria become damaged due to cellular stress, continued depolarization of their inner membrane occurs, leading to loss of mitochondrial ΔΨm, and this stabilizes PINK1 in the OMM.

There, PINK1 phosphorylates Mfn2 and then stimulates the ubiquitin-proteasome system UPS , which, in turn, recruits parkin to the OMM Ziviani et al. This further promotes the engulfment of damaged mitochondria by the phagophore or isolation membranes and hence the formation of mitophagosomes destined for removal via the lysosomal system.

Numerous studies have confirmed the roles of PINK1 and Parkin in mitochondrial quality control and mitophagy Sung et al. Mitochondrial quality control mechanisms that effectively sense and eradicate damaged mitochondria are weakened due to usage, aging, or disease, and this is likely to have a marked impact on neuronal health.

A growing body of evidence indicates that inhibition of the clearance of damaged mitochondria and the concomitant increase in ROS results in an accumulation of impaired neurons in AD.

One important aspect is that mitophagy could be compromised in AD due to unstable fusion of lysosomes and autophagosomes. Thus, disrupted lysosomal activity in healthy cells results in neuronal phenotypes resembling those in AD Nixon et al. In addition, autophagosome aggregation develops after oxidative stress in mouse cortical neurons, which shows similarities with AD Boland et al.

Together, these results indicate that impaired mitophagy is implicated in neuronal degeneration in AD Figure 3. The above analysis makes it clear that strategies capable of targeting mitochondrial function are needed to slow the progression of AD.

The focus of the research effort should be to develop a therapeutic intervention that can target ROS and excessive mitochondrial fragmentation, thereby minimizing mitochondrial dysfunction and consequent synaptic injury during AD progression summarized in Table 1.

One fascinating approach to reducing the burden of ROS and improving mitochondrial health is exercise. In the following section, we discuss in detail the impact of physical activity on mitochondrial function.

Exercise is one of the most effective strategies for maintaining a healthy body and normal brain activity. Moreover, exercise and a healthy diet can specifically boost several aspects of mitochondrial function.

In this context, the beneficial effects of caloric restriction and exercise in slowing the aging process and enhancing mitochondrial function have been shown in humans and rodent models Barbieri et al.

Significantly, exercise not only enhances mitochondrial activity in the peripheral organs, but also completely blocks brain atrophy in mouse models. The beneficial effects of physical activity are now widely accepted in humans as a way to not only improve fitness, but also treat patients with neurodegenerative diseases, including AD Bernardo et al.

Additional studies have reported numerous advantages of exercise in AD patients, including better blood flow to the brain, enhanced hippocampal thickness, enhanced neurogenesis, cognitive performance, reduced neuropsychiatric symptoms, and slower disorder Brown et al. It is well established that a sedentary lifestyle contributes to increased ROS and neuroinflammation seen in neurodegenerative disorders.

On the other hand, physical exercise can mitigate inflammation and oxidative stress Gleeson et al. This attenuation might be one of the mechanisms responsible for improving several clinical aspects, for instance, attenuating cellular aging Puterman et al.

Moreover, physical exercise prevented ROS and normalized its various components, including thiobarbituric acid reactive substances TBA-RS , superoxide dismutase SOD , catalase CAT , and glutathione peroxidase GPx in rats Mazzola et al.

Lack of exercise leads to an overall reduction in mitochondrial ETC activity in healthy individuals. Simultaneously, endurance training can improve ETC activity, and resistance training can stimulate the integration of satellite cells into existing muscle fibers.

Furthermore, exercise can stimulate mitochondrial proliferation through enhancing PGC-1α and AMPK signaling Kang and Li Ji, , and causes a reduction in the levels of systemic inflammation McGee et al.

This increase in PGC-1α and AMPK further promotes mitochondrial biogenesis. Adequate consumption of vitamins and minerals and the use of natural foods rich in antioxidants fruits, vegetables, etc. could represent the ideal approach to maintaining the optimal antioxidant status.

Foods that are rich in vitamin C can alleviate ROS. Vitamin C at various dosages, administered alone or in conjugation with other antioxidants, acutely or chronically, is the most commonly used antioxidant in clinical and laboratory research Carr and Maggini, ; Spoelstra-de Man et al.

Vitamin C attenuates ROS and maintains mitochondrial health in cells Kc et al. Similarly, Vitamin C consumption reduces Aβ plaque, preserves mitochondrial morphology, and ameliorates AD pathology in 5XFAD mice of AD Kook et al.

Moreover, the beneficial effect of caloric restriction on mitochondrial health is well documented. In addition to caloric restrictions, the ketogenic diet can slow down the development of cognitive dysfunction in patients with mild cognitive impairment MCI and AD.

Furthermore, ketone bodies have been shown to improve mitochondrial respiration, reduce the ROS production, improve antioxidant defense mechanism, and inhibit mPTP opening, thus ultimately protect mitochondrial and neuronal function Masino and Rho, Overall, these studies suggest that physical exercise and diet have beneficial effects on mitochondrial health, redox homeostasis, and neuronal function, supporting the adoption of a healthy lifestyle as an invaluable tool against AD.

Antioxidant therapies, innovative pharmacological strategies designed to boost mitochondrial function, and mitigate local ROS production in mitochondria competing to reduce global levels of ROS. These compounds include coenzyme CoQ10, idebenone, creatine, MitoQ, MitoVitE, MitoTEMPOL, sulforaphane, bezafibrate, latrepirdine, methylene blue, triterpenoids, a series of Szeto-Schiller SS peptides such as SS, curcumin, Ginkgo biloba, omega-3 polyunsaturated fatty acids Murphy and Hartley, and resveratrol which indirectly activates PGC-1α and induces mitochondrial biogenesis Lagouge et al.

Numerous laboratories have extensively evaluated these mitochondrial-targeted compounds using in vivo and in vitro models of AD. Advantages of these compounds include improving bioenergetics, reducing ROS, maintaining mitochondrial dynamics.

CoQ 10 is an essential cofactor of the ETC, functions by maintaining the mitochondrial ΔΨm, supporting ATP synthesis, and inhibiting ROS generation, thus protecting neuronal cells from oxidative stress and neurodegenerative diseases McCarthy et al.

Furthermore, it protects the membrane phospholipids, and mitochondrial membrane proteins against the damage of free radicals, increases mitochondrial mass and bioenergetic function Singh et al.

Other studies established that daily administration of CoQ10 significantly increased antioxidant enzyme activities and reduced inflammation Sohet et al.

Idebenone is an analog of CoQ10 that has better potency and a more promising pharmacokinetic profile. Idebenone can protect vision loss by enhancing mitochondrial ETC, in individuals with discordant visual acuities Klopstock et al. CoQ10 has been utilized in many disease states to reduce ROS and improve mitochondrial health; this warrants CoQ10 use in preclinical and controlled human trials.

Creatine in mitochondria combines with phosphate to form phosphocreatine, which functions as a source of high-energy phosphate released during anaerobic metabolism. Thus, creatine serves as an intracellular buffer for ATP and as an energy shuttle for the movement of high energy phosphates from mitochondrial sites of production to cytoplasmic sites of utilization.

Creatine is present in the highest concentration in tissues with high energy demands, such as muscle and brain Parikh et al. Studies suggest reduced phosphocreatine levels in muscle tissue were shown in individuals with mitochondrial dysfunction Tarnopolsky and Parise, , and administration with creatine monohydrate can enhance exercise capacity in some individuals with mitochondrial dysfunction Tarnopolsky, Similarly, beneficial effects of creatine supplementation have been shown in neurodegenerative and neurological diseases linked with mitochondrial dysfunction, such as PD, HD, and ALS Andres et al.

Findings from rodent research suggest that creatine exerts neuroprotective effects by buffering ATP levels to counter neurotoxic assaults by mPTP opening, and malonate Matthews et al. These data implicate that oral creatine may serve as a potential therapy against ROS and subsequent reduction of bioenergetics, which occurred in AD.

MitoQ is a mitochondria-targeted compound that enhances the mitochondrial protection against oxidative damage Cocheme et al. MitoQ consists of a lipophilic cation moiety that enables mitochondria-specific accumulation and ubiquinone converted to the antioxidant ubiquinol by the activity of complex II of the ETC Smith et al.

MitoQ, water-soluble that can be administered orally through the drinking water, and can cross the blood—brain barrier Rodriguez-Cuenca et al. Further, MitoQ prevented cognitive decline and neuropathology in a mouse model of AD McManus et al.

Treatment with MitoQ causes activation of cAMP response element-binding protein CREB , thus improve mitochondrial health Xing et al. Overall, these studies suggest the antioxidant and mitochondria protecting role of MitoQ in many pathological conditions, including AD.

Vitamin E belongs to a group of compounds that includes both tocopherols and tocotrienols Jiang, Tocopherol can protect cell membranes from oxidation, reacting with lipid radicals produced formed during lipid peroxidation Jiang, MitoVitE is basically the chromanol moiety of vitamin E that bounds to a triphenyl phosphonium TPP cation and accumulates within mitochondria due to the large negative charge of the IMM.

MitoVitE has been shown to accumulate in all major organs of mice and rats after oral, intraperitoneal, or intravenous administration and exerts a potent antioxidant activity Jameson et al. Trolox, a synthetic, water-soluble, and cell-permeable derivative of vitamin E, often serves as a potent antioxidant in several model organisms Wu et al.

MitoVitE was more effective in vitro and in vivo than trolox Jameson et al. MitoVitE can protect mitochondria from oxidative damage by reducing H 2 O 2 , inhibiting caspase activation, and blocking apoptosis Reddy, Another study demonstrates that MitoVitE can prevent the release of cytochrome c, and staving off apoptosis by inhibiting caspase-3 activation, thus, rejuvenating ΔΨm for effective bioenergetics Smith et al.

Importantly, antioxidants which specifically accumulate within the mitochondrial matrix are suggested to offer better protection against oxidative stress.

Sulforaphane, a natural isothiocyanate-derived from a glucosinolate found in cruciferous vegetables, particularly broccoli, which is considered to be a common activator of Nrf2, can combat oxidative damage in mitochondria Carrasco-Pozo et al.

The activation of the Nrf2 pathway leads to upregulation of many downstream products involved in protection against oxidative stress, including NAD P H quinone oxidoreductase 1 NQO1 , heme oxygenase 1 HO-1 , glutathione peroxidase 1 GPx1 , and gamma-glutamylcysteine synthetase γGCS Steele et al.

Sulforaphane has powerful antioxidant and anti-inflammatory properties, which allow it to reduce cytotoxicity and ROS dramatically. Animal studies suggest that sulforaphane supplementation could be disease-modifying for many common, devastating neurological conditions, such as AD, PD, epilepsy, stroke, etc.

Collectively, these results indicate that Nrf2 activators can have antioxidant effects by retaining mitochondrial redox homeostasis. Sulforaphane is a potential neuroprotective phytochemical that needs further human trials to determine its effectiveness in preventing and reducing the burden of multiple neurological diseases, including AD.

Through mitochondrial biogenesis, cells increase their mitochondrial population in response to increased energy demand. This is driven by the PGC-1α activation, which is a transcriptional coactivator that controls mitochondrial biogenesis. Bezafibrate, a peroxisome proliferator-activated receptor PPAR agonist widely used to treat dyslipidemia.

Bezafibrate supplementation resulted in the initiation of mitochondrial biogenesis, leading to an increase in mitochondrial mass, oxidative phosphorylation capacity, and energy generation Chaturvedi and Beal, ; Steele et al.

These findings imply that bezafibrate might be a promising therapeutic agent for treating any neurodegenerative diseases associated with mitochondrial dysfunction. SS is a small molecule that has been shown to exert potent antioxidant effects against ROS to protect mitochondrial function.

SS can prevent the peroxidase activity of cytochrome c in mitochondria, reduce ROS production, and aid reversal of mitochondrial dysfunction Szeto and Birk, Moreover, SS was proven to inhibit lipid peroxidation and hydrogen peroxide scavenging Reddy et al. SS has the benefit of being localized to the mitochondrion, explicitly targeting the IMM rather than the mitochondrial matrix.

Treatment with SS prevented mitochondrial dysfunction and enhanced ΔΨm, and increased neuroprotective gene PGC-1α in neuroblastoma N2a cells grown with mutant APP Manczak et al. It is worth noting that mitochondria-targeted small molecules such as SS, have been tested in cell culture and animal models of neurodegenerative diseases, such as AD, HD, PD, ALS, multiple sclerosis, and other human diseases.

Therefore, it is important to consider using small molecules for preclinical models and human clinical trials. In the last two decades, some inhibitors of Drp1, including, in particular, mitochondrial division inhibitor 1 Mdivi-1 , dynasore, diethyl 3,4-dihydroxyphenethylamino quinolinyl methylphosphonate DDQ , and P, have been developed, and their beneficial effects have been studied in cell cultures and mouse models.

The quinazolinone derivative, Mdivi-1, identified initially as a selective inhibitor of mitochondrial fission protein DRP1, induces neuroprotection in AD and PD models, as well as other neurodegenerative disorders, by improving mitochondrial fusion, and increasing mitochondrial biogenesis and synaptic protein levels Bido et al.

Recently, Mdivi-1 was shown to serve as a reversible mitochondrial complex I inhibitor that decreases mitochondrial fission and ROS production and further enhances mitochondrial function Bordt et al. In addition, recent detailed studies of neuronal N2a cells support the theory that Mdivi-1 inhibits mitochondrial heterogeneity and increases energy efficiency Manczak et al.

On the other hand, the capacity of Mdivi-1 to suppress Drp1 and trigger mitochondrial fission has recently been questioned Bordt et al. The authors did not notice any treatment effect with Mdivi-1 on mitochondrial morphology in mammalian cells in this study.

However, they confirmed the impact of Mdivi-1 on yeast Drp1, consistent with a previous report Cassidy-Stone et al. As Mdivi-1 is being considered for clinical trials, it may be appropriate to carry out more thorough investigations into its molecular targets to ensure its safety and effectiveness in humans.

Another cell-permeable small molecule that inhibits Drp1 activity is dynasore Macia et al. A low dose of dynasore is sufficient to inhibit mitochondrial fission caused by ROS in cultured cells Gao et al. Furthermore, dynasore inhibits mTORC1, which leads to nuclear translocation of TFEB and TFE3, the master regulators of autophagy and lysosomal biogenesis, thereby increasing autophagic flux.

Dynasore therapy greatly improves the clearance by autophagy of protein aggregates of mutant HD in cells Chen et al.

In this context, a recent study suggests dynasore treatment decreases Aβ internalization and processing to the secretory pathway. However, there is currently a lack of data on the impact of dynasore treatment on fission-fusion and mitophagy in early and late-onset AD.

Nevertheless, pharmacological interventions that inhibit the actions of Drp1 provide hope that excessive mitochondrial fragmentation can be abrogated in AD.

Finally, the inhibition of the fission mechanism will benefit mitophagy, and energy production. Recently, the role of mitochondrial dysfunction in AD has been studied using the pharmacological compound diethyl 3,4 dihydroxyphenethylamino quinolinyl methylphosphonate DDQ.

DDQ has shown promising effects on mRNA and protein levels associated with mitochondrial dysfunction and AD-related synaptic dysregulation. In addition, DDQ decreases mitochondrial fission proteins Drp1 and Fis1 , increases fusion proteins Mfn1 and 2 , and inhibit Aβ interactions.

A novel property of DDQ is that it binds at the active binding sites of Aβ and Drp1, inhibiting the formation of complexes between of Aβ and Drp1 Kuruva et al. This research indicates that DDQ can decrease the levels of Drp1 and Aβ, inhibit irregular Drp1-Aβ interactions, further decrease excessive mitochondrial fragmentation, and maintain mitochondrial function and synaptic activity in AD neurons.

The effect of DDQ either before or after Aβ treatment on levels of various mRNAs and proteins important for mitochondrial function PGC-1α, Nrf1, Nrf2, TFAM, DRP1, Fis1, Mfn1, and Mfn2 , as well as those involved in synaptic activation synaptophysin, PSD95, synapsin1 and 2, synaptobrevin1 and 2, synaptopodin, and GAP43 , has also been examined.

The mRNA and protein levels of mitochondrial-enhancing molecules such as PGC-1α, Nrf1, Nrf2, and TFAM were substantially increased following incubation with Aβ, followed by DDQ treatment. In addition, after DDQ therapy, a decrease in levels of mitochondrial fission proteins DRP1 and Fis1 and an increase in levels of mitochondrial fusion proteins Mfn1 and 2 was observed.

This led to the conclusion that in the presence of Aβ, pretreatment with DDQ decreases fission activity DRP1 and Fis1 and increases fusion activity Mfn1 and 2.

In order to evaluate its protective effects against Aβ-induced neuronal toxicity, more preclinical research using AD mouse models and clinical trials using AD patients treated with DDQ are needed. P is another inhibitor of Drp1, which acts by blocking the interaction of Drp1 and Fis1.

P was first used to protect neuronal cells: in cultured neurons, it reduces mitochondrial fragmentation and generation of ROS, restores mitochondrial integrity and ΔΨm, and protects cells against apoptosis caused by ROS Qi et al.

Other studies have used P to inhibit mitochondrial fission, thereby protecting the cell from death caused by stress or damage, especially in heart disease models. Moreover, treatment with P increases acute infarction-induced cell death and reduces heart failure both in vitro and in vivo Disatnik et al.

Therefore, P treatment should be assessed in early- and late-onset AD, at least in animal models, to confirm the therapeutic effects of this compound on mitochondrial fragmentation. Therapeutic interventions directed at the fusion machinery Mfn1, Mfn2, and OPA1 will enhance mitochondrial health by optimizing and rebalancing the regulation and control of fusion.

Drugs that improve mitochondrial fusion function have recently been documented to suppress the death of apoptotic cardiac cells in vivo. When the association between Mfn1 and βIIPKC is blocked by the novel agent SAMβA, mitochondrial fusion and cardiac function are enhanced in rats Ferreira et al.

Another promising compound, which modulates the activity of OPA1 in lung epithelial cells, is the small molecule BGP Szabo et al. Mechanistically, leflunomide inhibits pyrimidine synthesis; this minimizes the activity of doxorubicin-induced PARP and cleaved caspase in3 in embryonic mouse fibroblast MEF cells and shields PC12 cells from apoptosis Miret-Casals et al.

In , another mitochondrial fusion activator hydrazone M1 was introduced. Treatment with the fusion promoter M1 in this model reduces the release of cytochrome c and prevents cell death Wang et al. Similarly, M1 also protects mitochondrial function in a rotenone-induced PD model Peng et al.

These findings indicate that maintaining mitochondrial fusion is a promising approach to the treatment of a number of human diseases, including AD. Thus, further research is warranted, at least in animal models of AD, to test the effects of these drugs on impaired fusion machinery in AD.

Pharmacological agents and lifestyle interventions targeted at enhancing mitophagy are a promising approach for achieving a significant therapeutic benefit Kerr et al.

Caloric restriction, prolonged fasting, and physical exercise are bioenergetic challenges that can enhance neuroplasticity i.

For example, in mice, fasting and exercise result in elevated numbers of autophagosomes in cerebral cortical neurons, increased expression of SIRT3, and activation of mitochondrial biogenesis by a pathway involving BDNF signaling and PGC-1α upregulation Alirezaei et al.

Thus, exercise and fasting can augment the numbers of healthy mitochondria in neurons by promoting the pathways that enhance mitophagy. In addition, mitochondrial uncoupling agents, such as 2,4-dinitrophenol DNP , can induce autophagy and are useful in maintaining neuronal activity in animal AD models Geisler et al.

The mTOR inhibitor, rapamycin, is another mitophagy-inducing drug that can prevent cognitive defects and reduce Aβ pathology in an APP-mutant AD mouse model Spilman et al. Collectively, these results provide encouragement for controlled human trials to explore the therapeutic potential of the above compounds.

One approach that might accelerate the translation of these mitochondrial agents into the clinic is to screen compounds in animal models at the prodromal stage and after neurological symptoms.

If the drug impedes disease development in these models, there would be a firm basis for moving to human trials. We remain enthusiastic about the prospects for the treatment of neurodegenerative diseases using mitochondrial therapies; specifically, those designed to prevent mitochondrial damage, stimulate organelle biogenesis, and improve mitochondrial quality control Figure 4.

However, these advances require improvements in early diagnosis, the development of clinically appropriate biomarkers, and better trial design to allow for more rapid identification of compounds for the clinic.

Figure 4. Summary of physiological and pharmacological interventions and molecular targets to improve mitochondrial function in AD. We highlight several strategies that can contribute to mitochondrial health, such as exercise and a healthy diet, inhibition of excessive mitochondrial fragmentation and ROS, and improving fusion, biogenesis, transport, and mitophagy using various compounds, as potential strategies for AD prevention.

Apart from offering a cure, most therapeutic interventions can have numerous adverse side effects, which can also be the case with the use of some mitochondria-targeted therapeutics. Targetting mitochondria is a novel strategy; nevertheless, despite very encouraging results in using these mitochondrial-targeted therapeutics, it is challenging to target the population of damaged mitochondria selectively.

Notably, the targeting of compounds to the subcellular compartments represents one of the modern molecular pharmacology trends. The molecule would require exact physicochemical properties to cross the different barriers. For example, to suppress ROS, antioxidants administered orally or intraventricularly, or intra-muscularly, must travel through the blood and finally reach the targeted organ.

However, in this case, healthy tissues other than targeted organs that have not undergone oxidative damage, could be unavoidably targeted by frequent use of these antioxidants. As a result, upon increasing antioxidant doses to permit the repair of pathological mitochondria especially toxic hyperpolarized mitochondria , normal mitochondria may also be adversely affected, as their ROS levels may fall below their physiologically acceptable limit.

Undoubtedly, these compounds protected mitochondrial health and delayed aging in various animal trials; however, clinical evidence has not fully supported these preliminary findings. Thus, we have to be mindful of dosage, timing, and modes of exposure for different pathologies, with all the apparent benefits of mitochondrial-targeted therapeutics.

Significant progress has been made in discovering the causes of the debilitating neurodegenerative disorder AD. The exploration of treatments that target mitochondria in AD is in progress, but there is an immediate need to develop novel therapeutic approaches that block or slow down the progression of this incurable disease.

Here, we reviewed novel strategies for targeting altered pathways based on an aggregation of misfolded protein, defects in mitochondrial dynamics, OXPHOS dysfunction, oxidative stress, and compromised mitophagy in AD pathology.

It remains a significant challenge to develop mitochondrially targeted AD therapeutics using innovative drug delivery systems and transfer them from the lab bench to the hospital bed.

Nevertheless, in our opinion, focusing on mitochondria and expanding the area of mitochondrial pharmacology has enormous potential for modern, reliable mitochondrial therapy in AD.

AM, and LY designed the theme of the manuscript. LY conducted a critical revision of the manuscript. All authors contributed to the article and approved the submitted version.

Work on this manuscript was supported by grants from the National Natural Science Foundation of China , , and and the Guangdong Natural Science Foundation for Major Cultivation Project B The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Adlam, V. Targeting an antioxidant to mitochondria decreases cardiac ischemia—reperfusion injury. FASEB J. doi: PubMed Abstract CrossRef Full Text Google Scholar. Alirezaei, M. Short—term fasting induces profound neuronal autophagy.

Autophagy 6, — Physician 16, — Amigo, I. Caloric restriction increases brain mitochondrial calcium retention capacity and protects against excitotoxicity.

Aging Cell 16, 73— Andres, R. Functions and effects of creatine in the central nervous system. Brain Res. Arimon, M. Oxidative stress and lipid peroxidation are upstream of amyloid pathology. Assaly, R. Oxidative stress, mitochondrial permeability transition pore opening and cell death during hypoxia—reoxygenation in adult cardiomyocytes.

Barbieri, E. The pleiotropic effect of physical exercise on mitochondrial dynamics in aging skeletal muscle. Cell Longev. Beck, S. Bermejo, P. Gerontology 43, — Bernardi, P. The mitochondrial permeability transition from in vitro artifact to disease target.

FEBS J. Bernardo, T. Brain Pathol. Bertholet, A. Bido, S. Bleazard, W. The dynamin—related GTPase Dnm1 regulates mitochondrial fission in yeast. Cell Biol. Boland, B. Bordt, E. The Putative Drp1 Inhibitor mdivi—1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species.

Boutant, M. Mfn2 is critical for brown adipose tissue thermogenic function. EMBO J. Boyman, L. Dynamics of the mitochondrial permeability transition pore: Transient and permanent opening events. Broniowska, K. The chemical biology of S—nitrosothiols. Signal 17, — Brown, B.

Butterfield, D. Free Radic. Acta , — Trends Mol. CrossRef Full Text Google Scholar. Cai, Q. Cells Calkins, M. Calvo-Rodriguez, M. Canto, C. PGC—1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Carr, A.

Vitamin C and Immune Function. Nutrients Carraro, M. Measurement of membrane permeability and the mitochondrial permeability transition. Methods Cell. Carrasco-Pozo, C. Sulforaphane is anticonvulsant and improves mitochondrial function. Cass, S. Sports Med. Cassidy, L. Cassidy-Stone, A. Cell 14, — Castegna, A.

Chan, N. Broad activation of the ubiquitin—proteasome system by Parkin is critical for mitophagy. Charrin, B. Chaturvedi, R. Mitochondrial approaches for neuroprotection. Cheignon, C. Chen, H. Mitochondrial dynamics—-fusion, fission, movement, and mitophagy—-in neurodegenerative diseases.

Disruption of fusion results in mitochondrial heterogeneity and dysfunction. Chen, K. Role of mitofusin 2 Mfn2 in controlling cellular proliferation. Chen, Y. Dynasore Suppresses mTORC1 Activity and Induces Autophagy to Regulate the Clearance of Protein Aggregates in Neurodegenerative Diseases.

Cheng, A. Involvement of PGC—1alpha in the formation and maintenance of neuronal dendritic spines. Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges. Chu, C. Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases.

Chuang, Y. Resveratrol Promotes Mitochondrial Biogenesis and Protects against Seizure—Induced Neuronal Cell Damage in the Hippocampus Following Status Epilepticus by Activation of the PGC—1alpha Signaling Pathway.

Chung, C. Acute dynamin inhibition dissects synaptic vesicle recycling pathways that drive spontaneous and evoked neurotransmission. Cocheme, H. Mitochondrial targeting of quinones: therapeutic implications.

Mitochondrion 7, S94—S Cortes, L. Calcium Signaling in Aging and Neurodegenerative Diseases Cunnane, S. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Drug Discov. David, D. Proteomic and functional analyses reveal a mitochondrial dysfunction in PL tau transgenic mice.

Dei, R. Acta Neuropathol. Detmer, S. Functions and dysfunctions of mitochondrial dynamics. Cell Biol , 8, — Disatnik, M. Acute inhibition of excessive mitochondrial fission after myocardial infarction prevents long—term cardiac dysfunction. Heart Assoc. Du, H.

Signal 16, — Elgenaidi, I. Regulation of the phosphoprotein phosphatase 2A system and its modulation during oxidative stress: A potential therapeutic target? Fehrenbacher, K. Live cell imaging of mitochondrial movement along actin cables in budding yeast.

Ferreira, J. A selective inhibitor of mitofusin 1—betaIIPKC association improves heart failure outcome in rats. Ferrer, M. The double edge of reactive oxygen species as damaging and signaling molecules in HL60 cell culture. Cell Physiol.

Fiuza-Luces, C. Physical Exercise and Mitochondrial Disease: Insights From a Mouse Model. Flannery, P. Cell Neurosci. Frezza, C. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion.

Cell , — Fu, W. Mitochondrial Dynamics: Biogenesis, Fission, Fusion, and Mitophagy in the Regulation of Stem Cell Behaviors. Stem Cells Int. Galbusera, C. Increased susceptibility to plasma lipid peroxidation in Alzheimer disease patients. Alzheimer Res. Gamba, P. Gao, D. Dynasore protects mitochondria and improves cardiac lusitropy in Langendorff perfused mouse heart.

PLoS One 8:e Gauba, E. Gautier, C. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. A , — Geisler, J. Alzheimers Dement 13, — Gibson, G. Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age—associated neurodegenerative diseases.

Giorgi, C. The machineries, regulation and cellular functions of mitochondrial calcium. Gleeson, M. The anti—inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease.

Goldstein, L. Axonal transport and neurodegenerative disease: can we see the elephant? Gong, B. Gordon, B. The effects of exercise training on the traditional lipid profile and beyond. Guo, C. Cytoprotective effect of trolox against oxidative damage and apoptosis in the NRK—52e cells induced by melamine.

Guo, X. The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses. Neuron 47, — Gupta, V. Restoring polyamines protects from age—induced memory impairment in an autophagy—dependent manner.

Hallal, P. Global physical activity levels: surveillance progress, pitfalls, and prospects. Lancet , — Hansen, K. Transport of Proteins into Mitochondria. Protein J. Hollenbeck, P. The axonal transport of mitochondria. Cell Sci. Hroudova, J. Hu, C. Drp1—Dependent Mitochondrial Fission Plays Critical Roles in Physiological and Pathological Progresses in Mammals.

Huang, J. Iijima-Ando, K. PLoS One 4:e Ishihara, N. Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. Itoh, K. Mitochondrial dynamics in neurodegeneration. Trends Cell Biol. Jameson, V. Synthesis of triphenylphosphonium vitamin E derivatives as mitochondria—targeted antioxidants.

Tetrahedron 71, — Jiang, Q. Natural forms of vitamin E: metabolism, antioxidant, and anti—inflammatory activities and their role in disease prevention and therapy.

Jing, Y. Spermidine ameliorates the neuronal aging by improving the mitochondrial function in vitro. Proc Natl Acad Sci U S A , — Crouch PJ, Harding SM, White AR, Camakaris J, Bush AI, Masters CL.

Int J Biochem Cell Biol , — Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. Hum Mol Genet , — Rodrigues CM, Sola S, Brito MA, Brondino CD, Brites D, Moura JJ. Amyloid beta-peptide disrupts mitochondrial membrane lipid and protein structure: protective role of tauroursodeoxycholate.

Biochem Biophys Res Commun , — Apelt J, Bigl M, Wunderlich P, Schliebs R. Aging-related increase in oxidative stress correlates with developmental pattern of beta-secretase activity and beta-amyloid plaque formation in transgenic Tg mice with Alzheimer-like pathology.

Int J Dev Neurosci , — Matsuoka Y, Picciano M, La Francois J, Duff K. Neuroscience , — Takuma K, Yao J, Huang J, Xu H, Chen X, Luddy J, et al.

ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J , — Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology.

Bonda DJ, Wang X, Perry G, Smith MA, Zhu X. Drugs Aging , — Wang X, Su B, Fujioka H, Zhu X. Baldeiras I, Santana I, Proenca MT, Garrucho MH, Pascoal R, Rodrigues A, et al. Echtay KS. Mitochondrial uncoupling proteins—what is their physiological role?

Free Radic Biol Med , — Wu Z, Zhang J, Zhao B. Antioxid Redox Signal , — Piccolo G, Banfi P, Azan G, Rizzuto R, Bisson R, Sandona D, et al.

Biological markers of oxidative stress in mitochondrial myopathies with progressive external ophthalmoplegia. J Neurol Sci , 57— Smits P, Mattijssen S, Morava E, van den Brand M, van den Brandt F, Wijburg F, et al.

Functional consequences of mitochondrial tRNA Trp and tRNA Arg mutations causing combined OXPHOS defects. Eur J Hum Genet , — Wu SB, Ma YS, Wu YT, Chen YC, Wei YH.

Mitochondrial DNA mutation-elicited oxidative stress, oxidative damage, and altered gene expression in cultured cells of patients with MERRF syndrome. Mol Neurobiol , — Ikawa M, Arakawa K, Hamano T, Nagata M, Nakamoto Y, Kuriyama M, et al.

Evaluation of systemic redox states in patients carrying the MELAS AG mutation in mitochondrial DNA. Eur Neurol , — Wong A, Cavelier L, Collins-Schramm HE, Seldin MF, McGrogan M, Savontaus M-L, et al.

Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells. Deibel MA, Ehmann WD, Markesbery WR. Eskici G, Axelsen PH. Biochemistry , — Jomova K, Vondrakova D, Lawson M, Valko M.

Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem , 91— Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K, et al.

Opazo C, Huang X, Cherny RA, Moir RD, Roher AE, White AR, et al. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, et al. Cu II potentiation of alzheimer abeta neurotoxicity.

Correlation with cell-free hydrogen peroxide production and metal reduction. CAS Google Scholar. Lynch T, Cherny RA, Bush AI. Exp Gerontol , — Altamura S, Muckenthaler MU. PubMed Google Scholar. Pulliam JF, Jennings CD, Kryscio RJ, Davis DG, Wilson D, Montine TJ, et al. Am J Med Genet B Neuropsychiatr Genet , B: 48— Honda K, Casadesus G, Petersen RB, Perry G, Smith MA.

Ann N Y Acad Sci , — Wan L, Nie G, Zhang J, Luo Y, Zhang P, Zhang Z, et al. beta-Amyloid peptide increases levels of iron content and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease.

Sensi SL, Rapposelli IG, Frazzini V, Mascetra N. Sensi SL, Paoletti P, Bush AI, Sekler I. Zinc in the physiology and pathology of the CNS. Nat Rev Neurosci , — Goedert M, Spillantini MG. Science , — Petersen RB, Nunomura A, Lee HG, Casadesus G, Perry G, Smith MA, et al.

Cente M, Filipcik P, Pevalova M, Novak M. Expression of a truncated tau protein induces oxidative stress in a rodent model of tauopathy. Eur J Neurosci , — David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, et al.

Proteomic and functional analyses reveal a mitochondrial dysfunction in PL tau transgenic mice. Dumont M, Stack C, Elipenahli C, Jainuddin S, Gerges M, Starkova NN, et al. Behavioral deficit, oxidative stress, and mitochondrial dysfunction precede tau pathology in PS transgenic mice.

Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a PS tauopathy mouse model. Neuron , — Elipenahli C, Stack C, Jainuddin S, Gerges M, Yang L, Starkov A, et al.

Behavioral improvement after chronic administration of coenzyme Q10 in PS transgenic mice. Tuppo EE, Arias HR. El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD.

Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Johnstone M, Gearing AJ, Miller KM. A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced.

J Neuroimmunol , — Smits HA, Rijsmus A, van Loon JH, Wat JW, Verhoef J, Boven LA, et al. Amyloid-beta-induced chemokine production in primary human macrophages and astrocytes. Luo Y, Sunderland T, Roth GS, Wolozin B. Physiological levels of beta-amyloid peptide promote PC12 cell proliferation.

Kontush A, Schekatolina S. Puzzo D, Privitera L, Leznik E, Fa M, Staniszewski A, Palmeri A, et al. Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus.

Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidative damage is the earliest event in Alzheimer disease. Nunomura A, Tamaoki T, Tanaka K, Motohashi N, Nakamura M, Hayashi T, et al. Intraneuronal amyloid beta accumulation and oxidative damage to nucleic acids in Alzheimer disease.

Neurobiol Dis , — Castegna A, Aksenov M, Aksenova M, Thongboonkerd V, Klein JB, Pierce WM, et al. Part I: creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L Paola D, Domenicotti C, Nitti M, Vitali A, Borghi R, Cottalasso D, et al. Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells.

Nunomura A, Perry G, Pappolla MA, Friedland RP, Hirai K, Chiba S, et al. Neuronal oxidative stress precedes amyloidbeta deposition in Down syndrome.

Oda A, Tamaoka A, Araki W. Oxidative stress up-regulates presenilin 1 in lipid rafts in neuronal cells. J Neurosci Res , — Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, et al. Oxidative stress increases expression and activity of BACE in NT2 neurons.

Yoo MH, Gu X, Xu XM, Kim JY, Carlson BA, Patterson AD, et al. Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, Giliberto L, et al. Oxidative stress activates a positive feedback between the γ- and β-secretase cleavages of the β-amyloid precursor protein. Cole GM, Teter B, Frautschy SA.

Neuroprotective effects of curcumin. Adv Exp Med Biol , — Mandel SA, Amit T, Kalfon L, Reznichenko L, Youdim MB. Targeting multiple neurodegenerative diseases etiologies with multimodal-acting green tea catechins. J Nutr , S—S. Smith JV, Luo Y.

Studies on molecular mechanisms of Ginkgo biloba extract. Appl Microbiol Biotechnol , — Dumont M, Wille E, Stack C, Calingasan NY, Beal MF, Lin MT. Murakami K, Murata N, Noda Y, Tahara S, Kaneko T, Kinoshita N, et al.

Gamblin TC, King ME, Kuret J, Berry RW, Binder LI. Oxidative regulation of fatty acid-induced tau polymerization.

Schweers O, Mandelkow EM, Biernat J, Mandelkow E. Oxidation of cysteine in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments.

Melov S, Adlard PA, Morten K, Johnson F, Golden TR, Hinerfeld D, et al. Mitochondrial oxidative stress causes hyperphosphorylation of tau. PLoS One , 2: e Goedert M, Hasegawa M, Jakes R, Lawler S, Cuenda A, Cohen P. Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases.

FEBS Lett , 57— Wadsworth TL, Bishop JA, Pappu AS, Woltjer RL, Quinn JF. J Alzheimer Dis , — Yang X, Dai G, Li G, Yang E. J Mol Neurosci , — Yang X, Yang Y, Li G, Wang J, Yang E. Coenzyme Q10 attenuates β-amyloid pathology in the aged transgenic mice with Alzheimer Presenilin 1 mutation.

Gutzmann H, Kuhl KP, Hadler D, Rapp MA. Pharmacopsychiatry , 12— Senin U, Parnetti L, Barbagallo-Sangiorgi G, Bartorelli L, Bocola V, Capurso A, et al.

Idebenone in senile dementia of Alzheimer type: a multicentre study. Arch Gerontol Geriatr , — Thal LJ, Grundman M, Berg J, Ernstrom K, Margolin R, Pfeiffer E, et al.

Smith RAJ, Murphy MP. Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann N Y Acad Sci , 96— Okun I, Tkachenko SE, Khvat A, Mitkin O, Kazey V, Ivachtchenko AV. Curr Alzheimer Res , 7: 97— Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, et al.

Lancet , — Jones RW. Dimebon disappointment. Alzheimers Res Ther , 2: Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease.

J Clin Psychopharmacol , — Pettegrew JW, Klunk WE, Panchalingam K, Kanfer JN, McClure RJ. Neurobiol Aging , 1—4. Thal LJ, Carta A, Clarke WR, Ferris SH, Friedland RP, Petersen RC, et al. Thal LJ, Calvani M, Amato A, Carta A, Group ftA-l-CS.

A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, et al. N Engl J Med, — Abramova NA, Cassarino DS, Khan SM, Painter TW, Bennett JP.

Chen Z, Zhong C. Prog Neurobiol , 21— Download references. Department of Neurology, Zhongshan Hospital; The State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, , China.

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PubMed CAS Google Scholar Tholey G, Ledig M. Google Scholar Pratico D. PubMed CAS Google Scholar Nunomura A, Castellani RJ, Zhu X, Moreira PI, Perry G, Smith MA.

PubMed CAS Google Scholar Pocernich C, Butterfield D. PubMed Central PubMed CAS Google Scholar Behl C, Moosmann B. PubMed CAS Google Scholar Moosmann B, Behl C.

PubMed CAS Google Scholar Torres LL, Quaglio NB, de Souza GT, Garcia RT, Dati LM, Moreira WL, et al. PubMed CAS Google Scholar Beal MF.

PubMed CAS Google Scholar Beal M. PubMed CAS Google Scholar Butterfield D, Kanski J. PubMed CAS Google Scholar Zhao Y, Zhao B. PubMed Central PubMed Google Scholar Lovell MA, Ehmann WD, Butler SM, Markesbery WR. PubMed CAS Google Scholar Marcus DL, Thomas C, Rodriguez C, Simberkoff K, Tsai JS, Strafaci JA, et al.

PubMed CAS Google Scholar Pratico D, Clark CM, Lee VM, Trojanowski JQ, Rokach J, FitzGerald GA. PubMed CAS Google Scholar Williams TI, Lynn BC, Markesbery WR, Lovell MA.

PubMed CAS Google Scholar Omar RA, Chyan YJ, Andorn AC, Poeggeler B, Robakis NK, Pappolla MA. PubMed CAS Google Scholar Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, Radi E.

PubMed CAS Google Scholar Yan MH, Wang X, Zhu X. PubMed Central PubMed CAS Google Scholar Ayton S, Lei P, Bush AI. PubMed CAS Google Scholar Greenough MA, Camakaris J, Bush AI.

PubMed CAS Google Scholar Dias-Santagata D, Fulga TA, Duttaroy A, Feany MB. PubMed Central PubMed CAS Google Scholar Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM.

PubMed Central PubMed CAS Google Scholar Candore G, Bulati M, Caruso C, Castiglia L, Colonna-Romano G, Di Bona D, et al. PubMed CAS Google Scholar Lee YJ, Han SB, Nam SY, Oh KW, Hong JT.

PubMed CAS Google Scholar Ansari MA, Scheff SW. PubMed Central PubMed CAS Google Scholar Manczak M, Mao P, Calkins MJ, Cornea A, Reddy AP, Murphy MP, et al. PubMed Central PubMed Google Scholar Mattson MP. PubMed Central PubMed CAS Google Scholar Reddy PH.

PubMed Central PubMed Google Scholar Skoumalova A, Hort J. PubMed CAS Google Scholar Soderberg M, Edlund C, Kristensson K, Dallner G. PubMed CAS Google Scholar Butterfield DA, Reed T, Perluigi M, De Marco C, Coccia R, Cini C, et al. PubMed CAS Google Scholar Keller JN, Schmitt FA, Scheff SW, Ding Q, Chen Q, Butterfield DA, et al.

In line with this, the self-assembly of a tau fragment including the first and third tubulin-binding domains showed that the presence of HNE mediated polymerization of phosphorylated tau [ ]. At a molecular level, a link between phosphorylation and oxidative stress was revealed when a study showed that the activity of alkaline phosphatase was inhibited in the presence of HNE.

Exposure of tau to HNE hence resulted in the generation of a tau species resistant against dephosphorylation [ ]. Advanced glycation end products AGEs are the oxidation product of sugars that interact with proteins and their accumulation has been related to amyloid deposition in AD [ ].

Tau assembled into paired helical filaments has been shown to be immunoreactive against N ɛ - carboxymethyl lysine, one of the major AGEs [ ]. Interaction of recombinantly produced tau with ribose-derived AGE products was shown to result in the generation of reactive oxygen intermediates, which, in turn, activate NF κ b to induce amyloidogenic processing of AβPP to generate Aβ [ ].

Uptake of AGE-glycated tau into SH-SY5Y neuroblastoma cells was associated with malondialdehyde and HO-1 detection which was prevented by the exposure of these cells to N-acetylcysteine and probucol, two antioxidant compounds [ ].

Diffuse cytosolic immunoreactivity against AGE was shown in many neurons of post-mortem AD brains that also contain hyperphosphorylated tau [ ]. Astrocytes residing in the temporal cortex of medium to severely affected AD subjects were found to be immunoreactive for inducible nitric oxide synthase iNOS as well as AGEs [ ].

Thus far it is unclear whether AGE-glycation of tau has implications for the physiological role of this tubulin binding protein in the cytoskeletal organization or what the hierarchical correlation is between AGE formation and tau assembly into filaments.

Collectively, a clinical link between mitochondrial dysfunction and AD has been firmly established, with a central role for AD hallmark proteins Aβ and tau. While various types of ROS-mediated modifications of Aβ and tau have been investigated and play a potential role the precise implications of these species on disease progress have not been investigated.

AD brain originating neurons containing defective mitochondria show loss of dendritic spines and abbreviation of dendritic arborization [ ]. Differences in CA1 hippocampal mitochondria structure have been detected using 3-dimensional electron microscopy.

Instead of the uniformly elongated mitochondrial morphology observed in wild type mice, human AD brain and hippocampal mitochondria in mice carrying mutations for presenilin-1 psen1 , AβPP, and tau, have an ovoid or teardrop profile [ ]. Further, AD mouse models and AD patients show the presence of multiple small mitochondria and exaggerated mitochondrial division [ ] suggesting that the mitochondrial fission process is altered in AD.

The mitochondrial fission process relies on dynamin related protein 1 Drp1 and mitochondrial fission protein 1 Fis1 [ , ]. Recent research observed the presence of elongated interconnected organelles where multiple teardrop shaped mitochondria were connected by thin double membranes.

Even though altered mitochondrial fission processes in neurodegenerative diseases have been viewed primarily as a pathological feature, in cardiomyocytes Drp1 induced mitochondrial fission was shown to exert a protective effect against cellular apoptosis by enabling the cells to meet altered energetic demands [ ].

An alternative role of Drp1 was suggested with the observation that reduced association of Drp1 with the mitochondrial membrane induced a lack of mitochondrial fusion, which, in turn, induces high levels of mitochondrial oxidative stress [ ].

The fusion process should be in balance with mitochondrial fission to maintain mitochondrial homeostasis. Mitochondrial fusion is mediated by inner membrane fusion factor optic atrophy-1 OPA1.

Addition of H 2 O 2 to an osteosarcoma and a cardiomyoblast cell line lead to inhibited mitochondrial fusion as a result of loss of OPA1 activity through cleavage mediated by metalloendopeptidase OMA1 [ , ]. The endogenous antioxidant capacity is a multi-component system targeted at neutralizing ROS and RNS to prevent damage of cellular compartments.

Many of the factors involved in endogenous antioxidant capacity are affected in AD, and experimental evidence for this will be discussed in this section. Glutathione GSH is one of the prime endogenous antioxidants in the brain. GSH is a tripeptide thiol-containing antioxidant that is synthesized by the conjugation of the amino acids glutamate, cysteine, and glycine mediated by the enzymes γ -glutamyl cysteine synthetase and glutathione synthetase [ ].

GSH acts by scavenging ROS, and, in the process, becomes reversibly oxidized to form glutathione disulfate GSSG [ , ]. Oxidative stress induces the expression of the NADPH-dependent enzyme glutathione reductase, which reverts oxidized GSSG to its reduced form GSH [ ].

A study involving 74 human subjects demonstrated that GSH levels of autopsied brains did not significantly decrease with aging [ ]. At the same time, whole-brain GSH levels were shown to be profoundly reduced in individuals suffering from AD compared to age-matched controls [ ] although another study reports that GSH levels in AD brains are not significantly different from those found in age-matched control brains [ ].

Region-specific differences were identified showing increased GSH levels in the hippocampus and midbrain of AD patients without significant difference in GSSG levels [ ].

Moreover, a correlation between peripheral and brain levels of GSH exists as it was demonstrated that levels of erythrocytic GSH in elderly patients with MCI and AD were substantially decreased compared to a control group [ ]. A study investigating human AD patient lymphocytes showed that decreased GSH levels correlated with increased GSSG levels [ ].

Aging related reduction of brain GSH was shown to go hand in hand with decreased gene expression of γ -glutamyl cysteine synthetase in the brain [ ]. While whole-brain levels of GSH transferase in AD brains were not significantly different from age-matched control brains [ ], mRNA expression levels of γ -glutamyl cysteine synthetase vary per region in the brain with high expression levels in cortex, cerebellum and hippocampus and low expression in the neostriatum of mice [ , ], and it was suggested that these regional differences in de novo GSH generation can explain regional differences in susceptibility to oxidative stress [ ].

Melatonin, or N-acetylmethoxytryptamine, is involved in various homeostatic functions to aid cellular protection. It is an electroreactive neurohormone with antioxidant activity that is synthesized and secreted in the brain from mitochondria of pinaelocytes, cells of the pineal gland [ — ].

Also the metabolites of melatonin, N 1 -acetyl-N 2 -formylmethoxykynuramine AFMK and N 1 -acetylmethoxykynuramine AMK , demonstrate antioxidant activity, either directly by scavenging a variety of free radicals including hydroxyl, peroxyl, superoxide, peroxide and peroxynitrite ONOO - [ , ], or indirectly by inducing antioxidant enzymes including superoxide dismutase SOD , glutathione peroxidase GPx , and GSH reductase [ ], increasing GSH synthesis [ ], and inhibiting prooxidant enzymes RNS, xanthine oxidase, and myeloperoxidase [ ].

Even though aging is related to a decrease in CSF melatonin levels, presenile and senile AD patients demonstrated an even stronger reduction in melatonin levels that was shown to be dependent on apolipoprotein genotype [ ], one of the strongest identified genetic correlates with AD.

How these factors and processes are associated is currently unclear. The neuron-glial unit, the main interaction site between neurons and cells of glial origin such as astrocytes, regulates oxidative stress levels through an intimately linked intercellular mechanism for maintaining redox homeostasis [ , ].

Brain oxidative stress levels are maintained within strict limits as a result of the astrocytic nuclear factor erythroid 2 NFE2 -related factor 2 Nrf2 homeostatic pathway [ ]. Upon translocation to the nucleus, Nrf2 binds to antioxidant response element ARE , a promotor element present on antioxidant genes [ ].

Nrf2 degradation is controlled by ubiquitin-mediated degradation, which, in turn, is regulated by cytoskeleton associated Kelch-like protein, Keap1 [ — ].

In the absence of oxidative stress, Nrf2 is transcriptionally inactive as its activity is repressed by Keap1 [ ]. Under conditions of oxidative stress Keap1 is oxidized inhibiting the degradation of Nrf2.

Transcriptional activity of Nrf2 was shown to decline upon aging [ , ]. Furthermore, a recent transcriptomics study demonstrated that NRF2 knockout leads to early onset cognitive dysfunction, plaque deposition and tau tangle formation [ ]. Even though the Nrf2 signaling pathway is highly active in astrocytic cells, this pathway is virtually absent in cells of neuronal origin [ , ] while the capacity of neurons to degrade Nrf2 is high as a result of abundant neuronal expression of the protein cullin 3 which leads to destabilization of neuronal Nrf2 [ ].

These observations argue for a high level of functional integration of astrocytes and neurons in the brain to regulate oxidative stress levels. Disruption of metal ion homeostasis has been observed in various neurodegenerative disorders including AD [ ].

A multiphoton microscopy-based study using the genetically encoded calcium indicator Yellow Cameleon 3. This observation suggests a direct or spatial link between pathological alterations in neurons and the formation of senile plaques.

A second marker that indicates that there is a spatial link between AD-related deposits in the brain and neuronal functioning was the receptor for advanced glycation end products RAGE. Neuronal cells adjacent to senile plaques display increased RAGE expression while little change in expression was demonstrated in brain regions remote from plaques [ ].

Two other markers that have been used to topologically differentiate subpopulations of cells affected by oxidative stress include p50, which is a DNA binding subunit of transcription factor NF κ B [ , ], and HO Cellular structures containing accumulations of Aβ displayed increased levels of oxidative stress as demonstrated by elevated levels of HO-1, and p50 [ ].

Inactive NF κ B resides in the cytosol and is bound to inhibitory protein I κ B which prevents nuclear translocation of NF κ B. Phosphorylation, ubiquitination, and degradation of I κ B drives the activation of NF κ B [ ]. The redox state regulates activation and nuclear translocation of NF κ B [ ], and, as such, ROS was found to induce phosphorylation of I κ B via activation of responsible kinases [ , ].

Using p50 and HO-1, it was observed that the spatial link found between Aβ deposits and induction of cellular ROS is not limited to CSF residing neurons, but this observation extends to endothelial and smooth muscle cells in cerebral blood vessels. The expression of HO-1 was found to be elevated in AD injured neuronal cells, a feature that was more pronounced in regions close to neurofibrillary tangles and Aβ plaque deposits [ ].

A redox proteomics study of the brain of Down syndrome DS patients prior to onset of AD provided insight into the role of oxidative damage in the development of DS related early onset AD [ ].

Male and female DS and control brains were analyzed postmortem for carbonylation levels of proteins as hallmark of oxidative stress. DS brains showed increased carbonylation of six proteins including cathepsin D, glial fibrillary acidic protein and succinyl-CoAketoacid-coenzyme A transferase 1 mitochondrial protein.

Carbonylation affected protein functionality, while at the same time, proteasome activity and autophagy activity were decreased [ ] potentially leading to loss of functional protein.

Even though this study was conducted on a small number of subjects, it did provide important insight into the potential role of oxidative stress in early stages of disease. A larger scale study using human peripheral blood mononuclear cells PBMCs derived from MCI subjects similarly showed increased oxidative stress markers as detected by the fluorescent probe DCFH2-DA [ ].

Analysis of lymphocytes obtained from MCI subjects and AD patients similarly showed increased ROS levels, detected by 8OHdG, compared to lymphocytes derived from an age-matched control population [ ].

The validity of using 8OHdG brain levels as a biomarker to detect oxidative stress-related damage to DNA in AD patients has been questioned [ ].

However, the detection of increased levels in the frontal cortex of other modified macromolecules such as F2-isoprostanes as well as 3-NT and oxidized glutathione detected in patients with probable AD further corroborates the thought that oxidative stress is an early stage pathological feature of AD [ ].

The work by Ansari and Scheff also compared oxidative stress levels in age-matched groups with progressive forms of cognitive disorder, from non-cognitively impaired to AD, and showed that oxidative stress progressively worsened with cognitive decline. In addition to this, activities of SOD and catalase in post mitochondrial supernatant and in mitochondrial and synaptosomal fractions of the frontal cortex were significantly declined already in MCI subjects [ ].

Consistent with this, an earlier longitudinal study on autopsied control and patient brains demonstrated that levels of isoprostane F2 and F4-neuroprostane were increased in both amnestic MCI and late stage AD patients in various regions of the brain [ ].

The microcerebrovascular structure showed age-dependent changes [ ] which are more pronounced in cognitive disorders such as dementia [ , ]. For example, the basement membranes of cortical capillaries of patients suffering from cognitive disorders were significantly thicker than those of age-matched controls [ ].

Smooth muscle atrophy and general disorganization of these cells was consistently observed in AD subjects although these features seemed unrelated to the deposition of Aβ [ ]. The observed structural and functional changes in the microvascular organization thus lead to hypoperfusion and a general inability of the cerebral vasculature to meet the metabolic needs of the brain while this was partly compensated for by an increased ability to extract oxygen from the remaining blood flow [ ].

However, the remaining metabolic deficiency is of sufficient magnitude to result in neural hypoxia [ ]. Various conditions have been associated with increased brain oxidative stress and neuronal apoptosis in response to hypoxia, including sleep apnea [ , ], exposure to carbon monoxide [ ], and ischemia [ ].

Sleep apnea co-occurs frequently with AD [ ] while prevalence of sleep apnea positively correlates with aging [ , ], and treatment of sleep apnea slows down the rate of cognitive decline in patients diagnosed with mild-to-moderate AD [ ]. Further, hypoxia induced oxidative stress in the brain has been shown to induce cognitive deficits in rats [ ].

The mechanisms by which the brain adapts to hypoperfusion-induced hypoxia have been explored and most proposed mechanisms are centered around the thought that activation of hypoxia-inducible factor 1 α HIF-1 α plays an important role. HIF-1 α is a component of a heterodimeric complex with the aryl hydrocarbon nuclear translocator ARNT or HIFβ [ ].

Under normoxic conditions, HIF α is dissociated from this complex and unstable as a result of its hydroxylation which targets it for ubiquitination and proteasomal degradation [ — ].

Hypoxia prevents hydroxylation of HIF α by inhibition of the two hydroxylating enzymes, factor inhibiting HIF-1 and prolyl hydroxylase enzymes [ , ]. This stabilization induces its nuclear localization and heterodimeric complexation with ARNT.

Subsequent co-recruitment of this complex with transcription coactivators p and CREB binding protein CBP initiates gene transcription.

Hypoxic conditions are considered to raise cytosolic ROS levels and, in this way, induce the activation of HIF reviewed in [ ] probably in a mitochondrial complex III-dependent manner [ ]. The HIF-dependent hypoxia-inducible genes are generally involved in processes aimed at promotion cellular survival under hypoxic conditions.

A study investigating mRNA expression in adult rat brains upon occlusion of the middle cerebral artery demonstrated that glucose transporter-1 GLUT-1 and glycolytic enzymes phosphofructokinase, aldolase, and pyruvate kinase were upregulated to increase transport of glucose and glycolysis [ ].

This paragraph will first review the established experimental evidence that has demonstrated a connection between oxidative stress and AD, such as clusterin, apolipoprotein E ApoE , and genes related to AβPP processing machinery.

Second, this paragraph will also highlight some potential interactions that have yet to be experimentally established but for which observations have shown to connect to both AD and oxidative stress.

These factors include Klotho, and circadian clock genes and we envisage that future investigation into these factors and their relation to AD and oxidative stress levels may highlight alternative or additional mechanisms for the interaction of these clinical features.

Figure 1 summarizes the genetic factors associating AD and oxidative stress to date. These often involve the two hallmark proteins Aβ and tau and effects may be directly involving the generation of ROS or indirectly via interaction with various cellular factors giving rise to increased ROS generation or lowered endogenous antioxidant capacity.

Apolipoprotein J is a ubiquitously expressed secreted glycoprotein which is also known as clusterin CLU. Aging induces elevated levels of CLU gene expression [ , ] and plasma CLU [ ].

In a genome-wide association study CLU has been identified as a genetic determinant of AD [ ] and plasma CLU levels were associated with atrophy of the entorhinal cortex and clinical progression of the disease [ ] as well as with longitudinal brain atrophy in MCI patients [ ].

Apart from aging, expression of the CLU gene was demonstrated to be sensitive to heat-shock induced changes in the organism or the direct environment of the organism as a result of the presence of activating protein-1 AP-1 and CLU-specific element regulatory elements in its promotor [ ].

Multi-ligand receptor megalin has been identified to also act as receptor of clusterin [ ]. Various cellular stress stimuli have been shown to regulate transcriptional activity of AP-1 [ ].

Differential CLU expression was similarly observed in other oxidative stress-related pathologies including asthma [ ], atopic dermatitis [ ], diabetes type 2 [ ], coronary heart disease [ ], and cancer [ ].

Oxidative stress increases CLU expression. This was demonstrated in a study in which human diploid fibroblasts were treated with H 2 O 2 which resulted in increased mRNA levels of CLU [ ].

In human neuroblastoma cell lines SH-SY5Y and IMR both mRNA and protein levels of CLU were found to be upregulated in response to pro-oxidant pair iron-ascorbate [ ]. In line with these observations, CLU was originally identified to function as a chaperone protein where its activity was reported to depend on cellular redox state [ ].

CLU was shown to protect against oxidative stress in various cellular systems including fibroblasts and prostate cancer cells [ , ] but also in vivo in a Drosophila melanogaster model [ ].

In neuroblastoma N2a and SH-SY5Y cells knockdown of CLU by short hairpin RNA interference was found to down-regulate antioxidant capacity [ ]. The precise anti-oxidant mechanism of CLU is not known although blockage of the sulfhydryl groups contained in the sequence of the protein resulted in abolishment of its oxidative stress preventive activity [ ].

A review covering the involvement of CLU in oxidative stress detection and action has been published before [ ]. Apart from an antioxidative effect of CLU, an indirect role of CLU actually promoting oxidative stress has been described showing that the presence of CLU induces the formation of slowly sedimenting complexes composed of SDS-resistant synthetic Aβ assemblies that, in turn, induced oxidative stress in PC12 cells [ ].

Apolipoprotein E4 ApoE4 was identified as one of the major genetic risk factors for AD [ — ]. Apolipoprotein E exists in three isoforms, ɛ 2, ɛ 3, and ɛ 4, which vary in their amino acid composition.

Carriers of the ɛ 4-allele have an increased risk of developing AD [ ] as well as a decreased age of AD onset [ ] compared to non- ɛ 4 carriers. The pathogenic origins of ApoE4 have been studied to great length and indicate that ApoE4 is involved in processes such as aggregation and clearance of Aβ [ , ], mitochondrial dysfunction, and impairment of calcium [ , ] or cellular iron homeostasis [ ], and ApoE4 affects synaptic architecture and functioning [ , ].

A potential connection between the ApoE allele, AD, and oxidative stress was first deduced from the observation that the extent of oxidative stress and anti-oxidant defense is related to ApoE genotype in mice and in patients [ 13, , — ].

ApoE was demonstrated to act, directly or indirectly, as an antioxidant against hydrogen peroxide-induced cytotoxicity in a B12 ApoE expressing cell line [ ]. Elevated levels of peroxidized plasma low-density lipoproteins were observed in ApoE-deficient mice [ ].

Levels of lipid oxidation were significantly increased in the frontal cortex of AD patients that were homozygous or heterozygous for the ɛ 4-allele of ApoE compared to homozygous ɛ 3 carriers and controls [ 13 ]. Upregulation of catalase activity was exclusively observed in frontal cortex tissue of homozygous ApoE4 carriers while SOD activity and concentrations of glutathione were not different from that of controls [ 13 ].

Additionally, levels of HNE were increased in ɛ 4-carriers [ 84 ]. Further, mouse brain synaptosomes expressing human ApoE4 were more susceptible to Aβ 42 -associated oxidative stress than synaptosomes from mice expressing human ApoE2 or ApoE3 [ ].

Various experimental findings shed light on the potential molecular mechanism underlying these observations. They show involvement of thioredoxin-1 Trx1 , an endogenous antioxidant with a downregulating role in apoptosis signal-regulating kinase-1 Ask-1 [ ].

Thioredoxin reductases are reducers of Trx1 [ ]. Levels of Trx1 were reduced in AD brains [ , ] depending on ApoE genotype, but also in ApoE4 expressing mouse hippocampi, and human primary cortical neurons and neuroblastoma cells to which ApoE4 was supplemented with the culture medium, compared to ApoE3 [ ].

At the same time, Trx1 mRNA levels in ApoE4 TR mouse hippocampi were elevated consistent with findings reporting increased Trx1 expression in conditions of oxidative stress [ ]. Persson and colleagues suggested that increased mRNA levels of Trx1 potentially act as a compensatory mechanism for the increased cathepsin D-induced Trx1 turnover as observed in SH-SY5Y neuroblastoma cells [ ].

Moreover, Aβ was demonstrated to cause transient oxidation of Trx1 [ ] as well as ApoE4-induced downregulation of this protein which resulted in activation of an apoptotic pathway involving the translocation of Death-Domain Associated Protein-6 [ , , ] without affecting catalase and GSH activities [ ].

Individuals with DS are prone to develop early-age AD with pronounced oxidative stress. DS is characterized by trisomy of chromosome 21 HSA21 , which encodes AβPP as well as some proteins of relevance to redox homeostasis providing an interesting group of patients to study early stage aspects of oxidative stress in AD pathogenesis in response to a defined genetic condition.

Comparable to observations in AD patients, mouse models of DS demonstrated deficits in hippocampal learning and memory as well as neurodegeneration of cholinergic basal forebrain neurons [ , ]. DS patients display features of cellular energy impairment [ 4 ].

Recent transcriptomic profiling of the skeletal muscle of a DS mouse model showed that among the identified differentially expressed protein-coding genes in this tissue, two, Sod1 and Runx1, were implicated in oxidative stress [ ].

Chromosome HSA21 also codes for SOD explaining why expression levels of SOD are increased in DS [ ]. Transgenic mice overexpressing SOD1 demonstrate excessive levels of oxidative stress [ ] because concentrations of CAT and GPx, two enzymes that act to neutralize hydrogen peroxide, the product of SOD1 activity, do not rise accordingly.

Besides SOD1 fifteen other genes on HSA21 were predicted to play a role in mitochondrial energy generation and the metabolism of ROS [ ]. Levels of various ROS, RNS and aldehyde products of lipid peroxidation were found to be increased in brain [ 20, ] and urine [ ] of DS humans and animals [ ] indicating that oxidative stress may play a role in the pathogenesis of DS associated AD.

Levels of oxidative stress, i. However, a recent study showed that administration of melatonin at the pre- and post-natal stages partially alleviated oxidative stress but did not improve cognitive function in a mouse model [ ]. The process of programmed cell death was found to coincide with increased levels of oxidative stress, compared to control cells.

Programmed cell death could be rescued by administration of free radical scavengers including vitamin E, and N-tert-butylsulphophenylnitrone [ ] but dietary parameters did not alleviate oxidative stress biomarkers in young adult DS patients [ 20 ]. Similar to AD, the DS brain shows features of oxidative stress at very early stage.

For example, the DS fetal brain cortex was observed to show increased levels of thiobarbituric acid reactive substances TBARs , HNE, and protein carbonyl groups compared to controls [ ].

Also end-products of non-enzymatic glycation, pyrraline and pentosidine, were increased in DS fetal tissue [ ] and in amniotic fluid of DS pregnancies [ ]. Cells of both neuronal and non-neuronal origin exposed to H 2 O 2 or HNE generate increased levels of intracellular and secreted Aβ [ — ].

The role of oxidative stress in Aβ generation was further demonstrated in Tg mice, which overexpress a double mutated form of AβPP. Upon crossing this mouse line with a mouse in which one allele of MnSOD was knocked out, brain Aβ levels and Aβ plaque load were significantly increased [ ].

Similarly, hypoxia treated transgenic APP23 mice that were subjected to hypoxia conditions demonstrated increased memory deficits and deposition of Aβ into plaques [ ]. Vascular deposition of Aβ on the surface of cerebral endothelial cells results in vascular degeneration which has been observed in AD and leads to a condition termed cerebral amyloid angiopathy [ ].

Exposure of primary cerebral endothelial cells derived from 2-month-old Tg mouse brains to H 2 O 2 resulted in upregulation of AβPP expression and altered AβPP processing to favor the amyloidogenic pathway [ ].

Also in humans it was found that oxidative stress induced by hypoxia due to cardiac arrest increased serum Aβ levels [ ] suggesting that the machinery that generates this peptide is upregulated under pro-oxidative stress conditions in a wide range of disease models affecting various regions of the brain.

Aβ is generated as a heterogeneous pool of peptides which vary in the number of C-terminal amino acids. The two most prevalent types of Aβ are the amino acid Aβ and the amino acid Aβ isoforms.

It has been demonstrated that the longer Aβ peptide is inherently more amyloidogenic than Aβ These findings are potentially pathologically relevant as it was reported previously by our group and others that a marginally increased Aβ :Aβ ratio has severe implications for synaptotoxic response [ — ].

Aβ is generated by sequential cleavage of AβPP by two enzymes, γ -secretase and BACE, by a process termed amyloidogenic pathway. Alternatively, AβPP can be cleaved into an N-terminally truncated fragment of the Aβ peptide, called the p3 peptide, by γ - and α -secretase-mediated processing.

Details of AβPP processing have been extensively covered in a number of reviews [ 81, ]. Psen1 constitutes the catalytic site of the AβPP cleaving enzyme γ -secretase. In concerted action with BACE, psen1 is responsible for the generation of Aβ reviewed in [ ].

Clinical mutations in psen1 cause familial forms of early onset AD reviewed in [ ] and can affect γ -secretase mediated processing of AβPP in various ways [ ].

Generally, mutations in psen1 comprise the composition of the heterogeneous Aβ mixture by shifting the ratio between the various Aβ peptides generated [ — ].

However, a direct relation between hypoxia-induced oxidative stress and γ -secretase functionality exists. This was later demonstrated in zebrafish by showing that HIF-1 α induces increased mRNA expression levels of zebrafish related PSEN1 [ ].

Importantly, this factor plays a crucial role in the regulation of oxygen homeostasis and the expression and stability of one of the HIF-1 α domains is regulated by oxygen levels [ , , ].

Anterior pharynx-defective-1 APH1 is another component of γ -secretase and it was shown that Hela cells express increased levels of APH1 α in response to chemical hypoxia induced activation of HIF-1 α resulting in increased AβPP and Notch processing [ ]. NF-kB has been identified as important regulator of HIF-1 α expression [ ].

NF- κ B was shown to become activated and translocated to the nucleus in response to oxidative stress by addition of metformin, a pro-oxidative biguanide, to LAN5 neuroblastoma cells. This directly induced transcriptional activation of AβPP and psen1 and ultimately into increased AβPP cleavage, and intracellular accumulation of Aβ which promoted Aβ aggregation [ ].

BACE1 is an integral part of the amyloidogenic processing pathway of AβPP and the functionality of this enzyme was, similar to γ -secretase, reported to be affected by oxidative stress. This induction leads to an increased production of APP C-terminal fragments without affecting AβPP synthesis.

Pretreatment of these NT2 cells with α -tocopherol prevented BACE induction and CTF generation demonstrating direct involvement of oxidative stress in inducing BACE activity [ 81, ]. Various other publications similarly reported that BACE1 protein expression levels were increased in response to oxidative stress [ 80, , — ].

A similar observation has been reproduced in various model systems. For example, a developing h post fertilization zebrafish animal model exposed to hypoxia showed that the mRNA levels and activity of zebrafish bace1, the zebrafish orthologue to human BACE1, were affected by oxidative stress.

At the same time, the level of CAT was found to be increased upon exposure of zebrafish to hypoxia [ ]. Also, in murine primary cortical neuronal cultures, severe and cytotoxic levels of oxidative stress lead to an increased BACE1 expression.

Mild oxidative stress conditions were found to result in subcellular redistribution of BACE1 that promoted amyloidogenic processing of AβPP [ ]. Apart from in various animal and cellular models, increased BACE1 levels and activity were also found in brains of sporadic AD patients [ — ]. To understand the cellular signaling pathways involved in oxidative stress-regulated expression of BACE1, an NT2 cell-based assay was used.

P38 MAPK was also reported to be active and identified in Aβ deposits of AβPP tg mice [ ]. These observations are consistent with an earlier report that showed that Sp1 regulates transcription of BACE1, where expression levels of Sp1 were positively correlated with the generation of BACE1 and AβPP processing [ ].

In line with this, using a lipofuscinfluorphore A2E-mediated photo-oxidation model to investigate the role of BACE1 in age-related macular degeneration, it was shown that BACE1 expression is competitively regulated by Sp1 and DNA methyltransferase 1 DNMT1 after photo-oxidation [ ].

DNMT1 levels were reportedly decreased resulting in demethylation of specific loci within the BACE1 gene promotor [ ]. Moreover, members of the SAPK family were also found to be upregulated in AD patient brains [ 30, ] and are activated by various stress signals including oxidative stress [ , ].

The oxidative-stress regulated involvement of JNK has been further demonstrated in studies using transgenic mouse models. For example, JNK was found to be significantly activated in mutant AβPP tg mice with extensive oxidative damage but not in mutant AβPP tg mice with little oxidative damage [ ].

While it was consistently reported that the amyloidogenic processing pathway of AβPP is upregulated by various direct and indirect mechanisms, the non-amyloidogenic pathway, involving sequential cleavage of AβPP by α -secretase and γ -secretase, was found to be downregulated under conditions of oxidative stress [ ].

Multiple lines of evidence have shown that γ -secretase is upregulated under conditions of oxidative stress. As such, it was anticipated that the net lowering of the non-amyloidogenic processing of AβPP should be accommodated for by a decrease in α -secretase activity.

It was indeed shown that human neuroblastoma cell line SH-SY5Y exposed to hypoxic conditions decreases the expression of disintegrin and metalloproteinase domain-containing protein 10, or ADAM, also called α -secretase, in an O 2 -dose dependent manner [ ]. Similarly, human MSN cells exposed to oxidative stress induced by H 2 O 2 or FeCl 2 were shown to downregulate the active form of ADAM10 [ ].

Mechanisms that explain the downregulation of α -secretase under conditions of oxidative stress have not been explored in great detail. One of the hypotheses that has been postulated involves the JNK3-dependent phosphorylation of Thr of AβPP which is considered to be a direct target for BACE1 [ , ].

Even though the connection between circadian clock, oxidative stress, and AD has been little investigated and may not be directly related, the findings that have been reported on this topic show that a potential interaction between these features may well exist and warrants further investigation.

This paragraph summarizes the experimental evidence in supports of such a connection. Circadian rhythm disturbances and associated disorders of the sleep-wake cycle, i.

One report shows that extensive loss of sleep reduced the activity of SOD and the production of ATP in rat hippocampi [ ], features that are strikingly similar in the AD brain. In a follow-up report, apart from reduced SOD activity, it was found that the activity of glutathione peroxidase was also decreased while liver malondialdehyde levels were increased with the extent of sleep deprivation [ ].

On the other hand, brain and peripheral tissues were shown to differ in their peroxiredoxin oxidation rhythms [ ] as well as in other clock components [ ]. This means that peripheral observations cannot be automatically extrapolated to brain processes.

During periods of REM sleep firing rates of wake-active noradrenergic locus coeruleus neurons, cells that display high sensitivity to metabolic stress [ — ], are profoundly reduced [ ].

Extensive wakefulness induces loss of locus coeruleus neurons and sirtuin type 3 SirT3 was observed to be involved in this neurodegenerative process [ ].

Extensive deprivation of sleep is related to reduced levels of SirT3 in young adult wild type mice locus coeruleus neurons while oxidative stress levels increase presumably as a result of a combined increase in metabolic activity and decline in antioxidant response [ ].

Other circadian clock related factors associated with redox homeostasis of NAD cofactors include transcriptional activator complex BMAL1 and its binding partners CLOCK and NPAS2 [ ].

These clock genes were observed to be involved in glucose metabolism and redox homeostasis in peripheral tissues [ — ].

Expression levels of the master circadian clock regulator genes Bmal1 and Clock are significantly decreased in the cerebral cortex of aged mice [ ] although expression levels of these genes in AD brains have not been published. Mice generated with a deletion of Bmal1 demonstrated increased systemic [ , ] and low levels of brain oxidative stress [ ] mediated by a disturbance of its transcriptional targets, including Period Circadian Regulator 2 Per2 and albumin D-element binding protein Dbp [ ] as well as neuropathologies and synaptic degeneration [ , ].

For example, the kinetic occipital region in the brain of these Bmal1 knock-out mice showed a three-fold increase in level of F4-neuroprostanes when measured indicative of increased lipid peroxidation levels in neuronal cells [ ]. The deletion also resulted in increased neurodegeneration caused by mitochondrial 3-nitropropionic acid which was suggested to be a direct consequence of the decrease in BMAL1 transcription [ ].

Proteasome expression levels and activity were observed to follow circadian oscillations that correlated with the level of carbonylated proteins [ ] demonstrating that clearance of oxidized proteins are also showing circadian rhythm.

It would be of interest to investigate Bmal1 and Clock expression levels in AD patient brains to establish a possible connection between the observed symptoms of sleep deprivation in AD, oxidative stress status and cognitive dysfunction.

Klotho is a single-pass transmembrane protein hormone containing a long type I transmembrane domain and a short secreted domain [ ]. The latter is released into the extracellular space upon insulin-mediated release by ADAM family members ADAM10 and ADAM17 [ ].

Mutations in the KLOTHO gene were observed to induce a human aging resembling phenotype in a transgenic mouse model which could be genetically rescued by exogenous expression of klotho cDNA [ ]. Consistent with this, aging was found to be suppressed in a klotho overexpressing mouse model [ ].

Single nucleotide polymorphisms of KLOTHO affect trafficking and catalytic activity of klotho which was associated to onset of aging in a human population based study [ ]. Expression of the protein declines with age as was demonstrated by microarray analysis of the aging brain of a rhesus monkey model [ ].

Subsequently, the klotho gene has been dubbed an aging suppressor gene which acts by regulating oxidative stress [ ] because it was shown to effectively reduce urinary excretion of 8-OHdG upon renal overexpression in mice [ ].

This hypothesis was further supported by the finding that different cell types incubated with Klotho protein were protected from oxidative stress and apoptosis induced by paraquat [ ], hydrogen peroxide [ ], glutamate and oligomeric Aβ [ ].

Apart from in the kidney, the protein is also expressed in the choroid plexus in the brain with low levels of expression in the hippocampus [ , ]. In this brain region Klotho plays a role in hippocampus-dependent memory by regulating adult hippocampal neurogenesis [ ].

Mutation of klotho in a transgenic mouse model demonstrated increased levels of 8-OHdG and malondialdehyde in the hippocampus in an age-dependent manner [ ]. Klotho inhibits this pathway leading to activation of Forkhead box O FOXO transcription factor.

This, in turn, enhances the expression of ROS scavenging enzyme mitochondrial manganese SOD2 [ ] indicating that Klotho may perhaps lend its anti-aging capacity by indirect regulation of the generation of an antioxidant enzyme. One of the striking observations is that microglia in close proximity to amyloid plaques are often found to be activated and release O 2 ·— and H 2 O 2 [ ].

Clearly, the multicellular organization of the brain may be a relevant determinant in outcome of oxidative stress in AD, and potentially also other, neurodegenerative diseases.

For both Aβ and tau a number of potential contributory as well as inhibitory pathways in the process of oxidative stress generation have been proposed. Figure 1 provides an overview of the various cellular factors and mechanisms that are thought to associate oxidative stress and AD to date.

A potential anti-oxidant effect of Aβ has been attributed to the reported ability of Aβ to sequestrate redox-active metals [ 54, — ]. Heme- a , an essential component of mitochondrial complex IV, was shown to interact with Aβ , resulting in decreased assembly of this complex into a functional electron transport chain complex [ 90 ].

Both these protective and toxic roles of Aβ-metal complexation in oxidative stress receive ample support in the scientific field and perhaps the actual outcome whether metal ion binding is toxic is more subtly defined by factors such as Aβ level, Aβ aggregation state, co-occurring factors such as the availability of a reducing agent [ ], redox kinetics [ ], or disease stage.

Supportive of such a hypothesis is the observation that Aβ was found to act as a neurotrophic agent selectively at low nM concentrations while at higher peptide concentrations neurotrophic functionality was abolished [ , , ]. Even though the functional role of Aβ has been heavily debated, it has been argued that antioxidant activity may be the primary role of this peptide in the brain [ ].

However, a compelling finding arguing against an anti-oxidant function as primary role for Aβ was that oligomeric human Aβ, but not rodent Aβ, can bind two molecules of heme with sub μ M affinity which results in the generation of a peroxidase [ ].

Moreover, rat Aβ was reported to interact with zinc with lower affinity than human Aβ Such species specificity directly argues against a primary anti-oxidant role of Aβ although it does not rule out the potential of the peptide to also, next to its yet to identify primary role, demonstrate anti-oxidant activity via indirect routes.

Upon overexpression tau inhibits kinesin-dependent transport of mitochondria and peroxisomes into neuronal processes while the microtubular network remains intact [ ]. Lack of transport of these two organelles was shown to deplete neurites from ATP and protection mechanisms against oxidative stress as was illustrated by an increased vulnerability of tau overexpressing differentiated N2a cells upon exposure to H 2 O 2 [ ].

Another parameter proposed to play a role in tau-induced oxidative stress includes tau aggregation into paired helical filaments [ ]. Addition of synthesized HNE at micromolar concentrations to retinoic acid differentiated P19 embryonal carcinoma cells induced tau to crosslink into high molecular weight species [ ].

Crosslinking of tau into paired helical filaments was shown to be driven by abnormal levels of phosphorylation, or hyperphosphorylation, of tau, which renders the protein insoluble and dysfunctional [ , ].

The role of phosphorylation of tau in this process and the link to oxidative stress were highlighted by three subsequent publications showing that 1 phosphorylation of tau is partly regulated by the extracellular signal-regulated protein kinase ERK2 which becomes activated upon exposure to H 2 O 2 [ ], and also, 2 by rapid and potent activation of transcription factor NF κ B by reactive oxygen intermediate-mediated release of inhibitory factor I κ B from NF κ B [ ], and 3 acrolein, a peroxidation product of arachidonic acid, induced p38 stress-kinase-mediated tau phosphorylation [ ].

An in vitro follow up study demonstrated that co-incubation of a pseudo-phosphorylation mimicking form of tau with acrolein and methylglyoxal induced the formation of tau dimers and high molecular weight oligomers [ ].

Other than phosphorylation, also the glycation of tau was observed to connect tau tangle formation with oxidative stress. Using SH-SY5Y cells, advanced glycation end product-recognizing antibodies, increased HO-1 and malondialdehyde reactivity were shown to colocalize with tau paired helical filaments [ ].

A pioneering publication in used mass spectrometry and electron paramagnetic resonance spin trapping to demonstrate that Aβ in vitro under cell free conditions itself can fragment into free radical peptides in an oxygen-dependent but metal-independent manner [ ].

The generated Aβ fragment was capable of inactivating the enzymes glutamine synthetase and creatine kinase. The authors suggested that methionine 35 may be capable of reacting with oxygen to produce sulfoxide, which, in turn, can result in radical generation [ , ] although this hypothesis has not been experimentally verified.

Aβ was demonstrated to accumulate into various aggregation states ranging from monomeric to larger assemblies into amyloid plaques found upon postmortem analysis of AD patient brains.

In-between these two states an apparent continuum of oligomeric aggregates with different aggregation numbers, e. Detailed reviews have been published on this specific topic highlighting the potential toxic role of these intermediates and their relation with the clinicopathological features of AD [ — ].

Generally, experimental studies indicate that particularly the intermediate soluble aggregated forms of Aβ are highly toxic and these species are commonly referred to as oligomers or pre- or protofibrils [ , ].

More specifically, soluble SDS-stable dimers, extracted from AD brains [ ], up to 56 kDa soluble Aβ assemblies that are capable of inducing cognitive impairment in Tg mice [ ] have been identified as potential toxic species acting upon AD progress. While most of these studies merely investigate the association between assembly state and loss of cellular viability, synaptic function, or cognition, consistent with these observations, a study investigating the effects of different Aβ aggregate species on oxidative stress showed that specifically prefibrillar and oligomeric Aβ potently increased levels of oxidative stress in NT2 cells as detected by HNE and H 2 O 2 generation [ ].

Using a combination of electron spin resonance spectroscopy coupled to spin trapping, a short burst of H 2 O 2 generation was observed during early aggregation stages of Aβ [ ].

These Aβ and Aβ oligomers demonstrated prolonged disruption of phospholipid vesicles which is one of the proposed cytotoxic mechanisms of Aβ oligomers [ ]. However, the precise aggregation number of such Aβ oligomers is difficult to pin down using most standard biophysical and biochemical techniques as a result of their heterogeneous, dynamic, and interconverting nature.

Several mechanistically indirect pathways have been suggested by which means Aβ can influence mitochondrial function. Yeast-two-hybrid based screening of the human brain and a HeLa cell model demonstrated that Aβ and mitochondrial alcohol dehydrogenase may interact [ ]. This interaction was shown to be specific involving residues 12—24 of Aβ and disturbs the NAD-binding pocket and the catalytic triad of the enzyme leading to functional inhibition of nicotinamide dinucleotide binding required for the function of the enzyme [ , , , ], resulting in oxidative stress and neurodegeneration [ ].

Given the fact that Aβ is primarily an extracellularly generated peptide it is questionable whether Aβ and mitochondrial alcohol dehydrogenase may ever reside in close proximity of each other. Also, in these in vivo animal models Aβ was reported to co-localize with the N-terminus residues 98— and — of alcohol dehydrogenase while mutations within this site abrogated Aβ binding to alcohol dehydrogenase [ ].

Strengthening the suggestion that alcohol dehydrogenase may play a role in AD, degenerating neurons in the brains of AD patients were found to express up-regulated levels of alcohol dehydrogenase [ ], particularly those in close proximity to Aβ deposits [ ].

Although it cannot be ruled out that this observation represents an Aβ-unrelated compensatory mechanism to counteract the impaired energy homeostasis generally observed in AD neurons [ , ]. The role of alcohol dehydrogenase in AD has been more extensively covered in a review [ ]. The brain requires ATP and its intermediates for the formation of the neurotransmitter acetylcholine [ ], and the critical membrane component cholesterol [ ].

To accommodate these requirements it was recognized more than a century ago that the vascular system exerts some degree of plasticity to ensure sustained local activity of the neuronal network [ ]. Further, astrocytes, expressing GLUT1 type glucose transporters [ ], play a central role in neuronal energy supply [ ] supporting the notion that the multicellular context of the brain is highly supportive of neuronal energy-consuming activities.

Current PET and fMRI functional brain imaging techniques are based on the assumption that brain function is associated with brain energy consumption and from such techniques a wealth of information has been acquired over recent years on brain energy homeostasis in a variety of neurodegenerative disorders.

The association between oxidative stress and energy production becomes apparent when considering that the regeneration of GSH from GSSG is an NADPH dependent process, where NADPH is mainly obtained through glucose metabolism.

In various neurodegenerative disorders, including AD, a decrease in brain ATP generation is observed. Membrane fluidity changes observed upon iodoacetic acid-induced inhibition of ATP production could be rescued by treatment with anti-oxidants tirilazad and gossypol [ ] suggesting that reduced ATP availability may result in oxidative stress and membrane damage.

Upon aging, glucose metabolism derails progressively as a result of changes in brain insulin [ ], and cortisol [ ] levels. Also, activity of synaptic ATPases was significantly decreased in rat frontal cerebral cortex upon aging [ ].

Oxidative stress, induced by NO was shown to transiently reduce ATP generation in rat astrocytes while increasing glycolysis rate in an F 1 F 0 -ATPase and adenosine nucleotide translocase dependent manner specifically in primary astrocytes to rescue this ATP-depleted phenotype [ ]. At the same time, rat primary neurons exposed to NO were shown to progressively become ATP depleted which ultimately lead to cell death [ ].

A number of metabolism-related enzymes have been identified to be affected in a progressive manner in AD, including pyruvate dehydrogenase, ATP-citrate lyase and acetoacetyl-CoA thiolase [ ]. Activities of glycolysis and citric acid cycle related enzymes aldolase, triose phosphate isomerase, phosphoglycerate kinase, and phosphoglycerate mutase are affected in AD as a result of oxidation or nitration [ — ].

Inconsistent results have been published on phosphofructokinase activity in AD brains, with some researchers suggesting no significant reductions [ ]. Subcortical regions of the brain further displayed increased activities of hexokinase, an enzyme involved in the initiating step of glycolysis, and lactate dehydrogenase in AD patient brains while activities of these enzymes in cortical regions were unaffected [ ].

As the authors already suggest [ ], increased activity of lactate dehydrogenase is suggestive of a metabolic need for anaerobic respiration to compensate for lost ability to generate ATP via aerobic metabolic routes. Taken together, oxidation and nitration processes of many of the enzymes involved in cellular metabolism may reduce activity of such enzymes sufficiently to explain the significantly reduced ATP generation observed in AD brains while the bioenergetic adaptation of the cell towards anaerobic routes for obtaining sufficient quantities of ATP to sustain high levels of ATP generation cannot be sufficiently compensated for.

The question remains whether tau or Aβ only play an indirect role in activity reduction by inducing oxidation or nitration of these enzymes or whether a direct role, for example by activity-reducing interaction such as demonstrated for ABAD causes loss of metabolic rate.

A study using co-immunoprecipitation assays combined with tandem mass tag multiplexed quantitative mass spectrometry identified glycolysis enriched proteins such as pyruvate kinase and aldolase as potential interactors with tau [ ].

Using ELISA and gel filtration assays, it was reported that synthesized Aβ 42 and Aβ can interact in vitro with a K D of 5 nM with rat phosphofructokinase, but not lactate dehydrogenase [ ]. It is still debatable what the triad of factors oxidative stress, Aβ or tau and cellular metabolism exactly comprises in terms of molecular interactions and how they reciprocatively interact with each other.

One attempt to address this question was published by Casley and colleagues who incubated isolated rat brain mitochondria either with Aβ or Aβ with or without NO to determine the relative impact of each of these factors on mitochondrial respiration using oxygen sensitive electrodes [ ].

Both Aβ peptides significantly inhibited mitochondrial respiration by specifically affecting the activity of complex IV, while exposure of the mitochondria to NO substantially worsened respirational outcome.

RAGE is a transmembrane receptor widely expressed in all tissue types including the brain [ , ]. One diverse group of ligands known to interact with this receptor are advanced glycation end products, AGEs.

AGEs are the product of non-enzymatic aldose-mediated glycated or oxidized proteins [ ], and accumulation of AGEs was shown to be aging-related [ , ] and accelerates in conditions such as diabetes [ ].

Potential clinical relevance of RAGE to AD was demonstrated using ELISA of AD brain homogenates showing a 2. The roles of RAGE and AGEs in AD pathogenesis have been covered in a number of reviews [ , ].

The offspring of a transgenic RAGE overexpressing mouse model crossed with Tg APP animals showed neuronal perturbation already at months of age, and astrogliosis and reactive microglia at 14—18 months [ ].

One of the general observations is that Aβ can interact with RAGE. For example, Yan and co-workers have shown that endothelial or PC12 RAGE provides a binding site for I-labeled synthetic Aβ on cellular surfaces. This interaction was found to result in cellular perturbation and dose-dependent generation of TBARS, NF- κ B-mediated microglial activation, and cytotoxicity.

TBAR generation could be blocked by pre-treatment of cultures with antioxidants probucol or N-acetylcysteine [ ] demonstrating a direct or indirect association with oxidative stress. Indeed, interaction of Aβ with RAGE on the cell-surface exerted localized oxidant activity. The authors further observed that stimulation of RAGE by other ligands which do not themselves generate ROS induces intracellular generation of oxidants in target cells [ ] suggesting that it is the interaction between RAGE and its ligand that induces the oxidation effect and not the ligand by itself.

Not only Aβ as AD hallmark peptide appeared to show an association with RAGE-induced oxidative stress: using immunostaining it was shown that tau paired helical filaments colocalize with AGEs in AD temporal cortex tissue [ ].

Also, tau was shown to be amenable to ribose-mediated glycation and exposure of SH-SY5Y cells to these glycated tau species resulted in oxidative stress without affecting cell viability [ ]. It appears that AGE-RAGE interaction with AD hallmark partners results in a variety of cellular responses that can mediate oxidative stress.

In turn, cellular metabolic rate was shown to be directly proportional to ROS generation in rat and porcine lung [ ], and hepatomas [ ].

Apart from neurons, astrocytes also play an ion regulating role supporting neuronal activity. Its molecular composition and mechanism of action have been under debate in the last years.

Initially, the mPTP was thought to consist of the voltage-dependent anion channel VDAC in the outer membrane, the adenine nucleotide translocase ANT in the inner membrane and Cyclophilin D CypD in the matrix.

In this way, when CypD translocates to the inner mitochondrial membrane to interact with ANT and VDAC [ ], the mPTP opens allowing non-selective exchange of calcium [ — ].

More recent findings dismiss this initial idea and indicate that VDAC is not a key component of the mPTP [ , ] and ANT has only a regulatory function rather than being a core unit of the mPTP [ ].

Only CypD, a peptidyl-prolyl isomerase F located in the mitochondrial matrix, remains a critical molecule in the mPTP in both postulations. Consistent with this, studies in animal models have shown that mPTP formation can be efficiently blocked by the addition of a cyclophilin D inhibitor, cyclosporine A CSA or by depletion of CypD [ , , ].

However, prolonged mPTP leaking may result in mitochondrial disruption. In this regard, increased CypD expression has been identified in neurons of the hippocampus and temporal lobe of AD patients [ ].

CypD was shown to specifically bind to Aβ oligomers both in vitro and in vivo in a dose-dependent manner facilitating permeability transition and ROS formation causing mitochondrial dysfunction [ — ]. The role of ROS was highlighted by demonstrating rescue of Aβ-induced loss of axonal mitochondrial movement upon administration of Probucol, an anti-oxidant agent [ ].

Oxidative stress is an early clinical feature of AD, as well as other neurodegenerative disorders. AD-related oxidative stress arises as a result of increased generation of ROS, induced by mitochondrial failure, but also decreased levels of endogenous antioxidants are commonly observed in AD.

Many of the biomacromolecules that are part of normal cellular physiology are susceptible to oxidative modification altering their function.

Also, Aβ and tau, two AD hallmark proteins are subject to oxidation, while Aβ itself was reported to induce the formation of ROS.

A number of genetic factors have been identified to play a role in AD-related failure to maintain physiological ROS levels within strict limits. For example, clusterin, apolipoprotein E, klotho, and enzymes involved in the AβPP processing machinery regulating Aβ generation are related, either directly or indirectly, to oxidative stress.

Various molecular mechanisms explaining the association between oxidative stress and AD have been identified. The association between oxidative stress and AD appears complex, bi-directional, and self-reinforcing.

Work related to oxidative stress in the group of the corresponding author is financially supported by a ZonMw Memorabel grant number Lancet , — Neuroscience , — Biochim Biophys Acta , 2— Neurobiol Dis , — Biochim Biophys Acta , — Mariani E , Polidori MC , Cherubini A , Mecocci P Oxidative stress in brain aging, neurodegenerative and vascular diseases: An overview.

J Chromatogr B , 65— Ageing Res Rev 8: , — Proc Natl Acad Sci U S A , — Shah K , Kumar RG , Verma S , Dubey RS Effect of cadmium on lipid peroxidation, superoxide anion generation and activities of antioxidant enzymes in growing rice seedlings. Aging 66 , — Claxton, A.

Biliverdin reductase-A mediates the beneficial effects of intranasal insulin in Alzheimer disease. This paper improves our mechanistic understanding of the beneficial effects of intranasal insulin in the cognitive improvement of patients with AD and MCI by demonstrating in the 3xTg mouse model of AD that BVRA was prevented from early impairment in adult mice, or rescued from damage in aged mice, following intranasal insulin that was correlated with improved insulin signalling, decreased nitrosative stress and improved cognition.

Article PubMed Google Scholar. Impairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: a new paradigm. Cunnane, S. Can ketones compensate for deteriorating brain glucose uptake during aging? NY Acad. Wu, L. Lu, D. A second cytotoxic proteolytic peptide derived from amyloid β-protein precursor.

Nikolaev, A. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Intlekofer, K. Opii, W. Aging 29 , 51—70 Solomon, A.

Effect of the Apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: a subgroup analysis of a randomized clinical trial.

JAMA Neurol. Scarmeas, N. Nutrition and prevention of cognitive impairment. Fyfe, I. APOE ε4 affects cognitive decline but does not block benefits of healthy lifestyle. van Dalen, J. Effect of long-term vascular care on progression of cerebrovascular lesions: magnetic resonance imaging substudy of the PreDIVA trial prevention of dementia by intensive vascular care.

Stroke 48 , — Chu, C. Use of statins and the risk of dementia and mild cognitive impairment: a systematic review and meta-analysis.

Cholesterol-independent neuroprotective and neurotoxic activities of statins: perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders.

Biliverdin reductase-A: a novel drug target for atorvastatin in a dog preclinical model of Alzheimer disease. Redox proteomics and amyloid β-peptide: Insights into Alzheimer disease. Gordon, B. This paper reports longitudinal PET and MRI results on brains in persons with autosomal dominantly inherited AD obtained regularly 22 years before up to 3 years after the onset of AD symptoms and demonstrates the temporal order of brain pathology observed prior to symptoms.

Zhang, H. Davies, M. Protein oxidation and peroxidation. This article provides a very good account of the mechanisms and consequences of oxidative protein damage. Milne, G. The isoprostanes—25 years later. This paper provides an excellent review of the formation of isoprostanes in biological systems and their role as biomarkers of lipid peroxidation in disease.

Dizdaroglu, M. Measurement of oxidatively induced DNA damage and its repair, by mass spectrometric techniques. This article provides a detailed and comprehensive review of mechanisms of oxidative DNA damage and how it can be measured in vivo. Ishii, T. Specific binding of PCBP1 to heavily oxidized RNA to induce cell death.

Natl Acad. USA , — Wang, J. Oxidative modification of miR enables it to target Bcl-xL and Bcl-w. Cell 59 , 50—61 Dai, D. Transcriptional mutagenesis mediated by 8-oxoG induces translational errors in mammalian cells. Download references. This work was supported in part by grants from the US National Institutes of Health 1R01 AG; D.

and the National Medical Research Council and Tan Chin Tuan Centennial Foundation, Singapore B. The authors thank X. Ren for assistance with Figures 1—3 and the three reviewers for their very helpful suggestions. Nature Reviews Neuroscience thanks R. Martins, and the other anonymous reviewers, for their contribution to the peer review of this work.

Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. Department of Biochemistry and Centre for Ageing and Neurobiology, National University of Singapore, Singapore, Singapore. You can also search for this author in PubMed Google Scholar. Correspondence to Barry Halliwell.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Cognitive processes that include planning, reasoning and problem solving that in humans largely involve the prefrontal cortex, with connections to other brain areas.

Oxygen-containing species that contain unpaired electrons which makes them free radicals or from which free radicals are easily derived. Nitrogen-containing species that are free radicals or moieties from which free radicals are easily derived. A method for identification of oxidatively modified proteins that most often involves protein separation and digestion, mass spectrometric utilization to sequence the amino acids of the resulting peptides and protein identification and informatics.

One of the components of the proteostasis network; involves formation of a double membrane autophagosome that surrounds the aggregated, damaged protein or organelle and transport of the autophagosome to and fusion with a lysosome, exposing the contents of the autophagosome to proteolysis and degradation.

Sometimes called protein quality control, proteostasis is a term encompassing three different cellular processes the ubiquitin—proteasome system, autophagy and the endoplasmic-reticulum-resident unfolded-protein response used to degrade aggregated, damaged proteins or sometimes cellular organelles.

Reprints and permissions. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci 20 , — Download citation. Published : 08 February Issue Date : March Anyone you share the following link with will be able to read this content:.

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Subjects Alzheimer's disease Neural ageing. Abstract Alzheimer disease AD is a major cause of age-related dementia.

Access through your institution. Buy or subscribe. Change institution. Learn more. References Nelson, P. CAS PubMed PubMed Central Google Scholar Martins, R. CAS PubMed PubMed Central Google Scholar Markesbery, W. PubMed PubMed Central Google Scholar Landau, S. Google Scholar Weise, C.

PubMed PubMed Central Google Scholar Croteau, E. CAS PubMed Google Scholar Arnold, S. CAS PubMed PubMed Central Google Scholar Halliwell, B.

CAS PubMed PubMed Central Google Scholar Cheignin, C. Google Scholar Halliwell, B. CAS PubMed Google Scholar Butterfield, D. CAS PubMed PubMed Central Google Scholar Nourooz-Zadeh, J. CAS PubMed Google Scholar Di Domenico, F. PubMed Google Scholar Di Domenico, F. PubMed Google Scholar Lauderback, C.

CAS PubMed Google Scholar Martins, R. CAS PubMed Google Scholar Smith, M. Google Scholar Hensley, K. CAS PubMed Google Scholar Sultana, R.

CAS PubMed Google Scholar Bradley, M. CAS PubMed PubMed Central Google Scholar Reed, T. PubMed Google Scholar Sultana, R. CAS PubMed PubMed Central Google Scholar Lyras, L. CAS PubMed Google Scholar Santos, R.

CAS PubMed Google Scholar Abolhassani, N. CAS PubMed Google Scholar Shan, X. CAS PubMed Google Scholar Nunomura, A. CAS PubMed Google Scholar Li, S. CAS PubMed PubMed Central Google Scholar Bereczki, E. PubMed PubMed Central Google Scholar Yang, T. CAS PubMed PubMed Central Google Scholar Di Domenico, F.

PubMed Google Scholar Reed, T. CAS PubMed Google Scholar Neth, B. PubMed PubMed Central Google Scholar Lee, J.

Google Scholar Bezprozvanny, I. CAS PubMed PubMed Central Google Scholar Pirollet, F. CAS PubMed Google Scholar Tramutola, A. PubMed Google Scholar Nixon, R. CAS PubMed PubMed Central Google Scholar Rabbani, N.

CAS PubMed PubMed Central Google Scholar Yan, S. CAS PubMed Google Scholar Pugazhenthi, S. CAS Google Scholar Piras, S. CAS PubMed Google Scholar Emendato, A. CAS PubMed PubMed Central Google Scholar Sweeney, M.

CAS PubMed PubMed Central Google Scholar Bonet-Costa, V. CAS PubMed PubMed Central Google Scholar Keller, J. Google Scholar Tseng, B. CAS PubMed Google Scholar Mota, S.

CAS PubMed Google Scholar Hashimoto, S. PubMed PubMed Central Google Scholar Di Domenico, F. Google Scholar Choi, J. CAS PubMed Google Scholar Castegna, A.

CAS PubMed Google Scholar Gerakis, Y. CAS PubMed Google Scholar Wiseman, F. PubMed PubMed Central Google Scholar Lott, I. PubMed PubMed Central Google Scholar Perluigi, M. CAS PubMed PubMed Central Google Scholar Busciglio, J.

CAS PubMed Google Scholar Perluigi, M. CAS PubMed Google Scholar Barone, E. CAS PubMed PubMed Central Google Scholar Vlassenko, A. CAS PubMed PubMed Central Google Scholar Caraci, F. CAS PubMed Google Scholar Nakamura, A.

CAS PubMed Google Scholar Hamlett, E. CAS PubMed Google Scholar Winblad, B. PubMed Google Scholar Golzan, S. PubMed PubMed Central Google Scholar Koronyo, Y. PubMed Google Scholar Tang, M. PubMed PubMed Central Google Scholar Chhatwal, J.

PubMed PubMed Central Google Scholar Casamitjana, A. CAS PubMed Google Scholar Polidori, M. CAS PubMed Google Scholar Petersen, R. CAS PubMed Google Scholar Sano, M.

Google Scholar Ulatowski, L. CAS PubMed Google Scholar Spector, R. CAS PubMed Google Scholar Pei, R. CAS PubMed PubMed Central Google Scholar Schaffer, S. CAS PubMed Google Scholar Mattson, M. CAS PubMed PubMed Central Google Scholar Begum, A.

CAS PubMed PubMed Central Google Scholar Nelson, K. CAS PubMed PubMed Central Google Scholar Ma, Q. Google Scholar Branca, C. CAS PubMed PubMed Central Google Scholar Long, L. CAS PubMed Google Scholar Halliwell, B. CAS PubMed Google Scholar Cheah, I. CAS PubMed Google Scholar Valero, T.

CAS Google Scholar Huang, Z. CAS PubMed Google Scholar Ng, L. CAS PubMed Google Scholar Raefsky, S. CAS PubMed PubMed Central Google Scholar Claxton, A. PubMed PubMed Central Google Scholar Barone, E. Article PubMed Google Scholar Barone, E. CAS PubMed Google Scholar Cunnane, S.

CAS PubMed Google Scholar Wu, L. CAS PubMed PubMed Central Google Scholar Lu, D. CAS PubMed Google Scholar Nikolaev, A. CAS PubMed PubMed Central Google Scholar Intlekofer, K. CAS PubMed Google Scholar Opii, W.

CAS PubMed Google Scholar Solomon, A. PubMed PubMed Central Google Scholar Scarmeas, N. PubMed Google Scholar Fyfe, I. Google Scholar van Dalen, J. PubMed Google Scholar Chu, C. PubMed PubMed Central Google Scholar Butterfield, D. CAS PubMed PubMed Central Google Scholar Barone, E.

Article PubMed Google Scholar Gordon, B. PubMed PubMed Central Google Scholar Zhang, H. PubMed PubMed Central Google Scholar Davies, M. CAS PubMed PubMed Central Google Scholar Milne, G. CAS PubMed Google Scholar Dizdaroglu, M.

CAS PubMed Google Scholar Ishii, T. PubMed Google Scholar Wang, J. CAS PubMed Google Scholar Dai, D. CAS PubMed Google Scholar Download references. Acknowledgements This work was supported in part by grants from the US National Institutes of Health 1R01 AG; D.

Reviewer information Nature Reviews Neuroscience thanks R. Author information Authors and Affiliations Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA D.

Allan Butterfield Department of Biochemistry and Centre for Ageing and Neurobiology, National University of Singapore, Singapore, Singapore Barry Halliwell Authors D.

Allan Butterfield View author publications. View author publications. Ethics declarations Competing interests The authors declare no competing interests. Glossary Higher executive functioning Cognitive processes that include planning, reasoning and problem solving that in humans largely involve the prefrontal cortex, with connections to other brain areas.