Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease

Caspersen, Casper; Wang, Ning; Yao, Jun; Sosunov, Alexander A.; Chen, Xi; Lustbader, Joyce W.; Xu, Hong; Stern, David M.; McKhann, Guy M.; Yan, Shi Du

doi:10.1096/fj.05-3735fje

Cited by 684 publications

(608 citation statements)

References 74 publications

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“…60 Recent publications and our findings describe a mitochondrial localization for APP 61 (Supplementary Figure 1), for a functional g-secretase complex 62 and for Ab. 63,64 Thus APP and Ab in mitochondria could inhibit the ATP synthase subunit a within the F 1 F 0 -ATP synthase complex of the electron transport chain, resulting in ATP depletion. It is noteworthy in this respect that mitochondria in cultured neurons display spontaneous changes in mitochondrial membrane potential, 65 which are impaired in mitochondria from Alzheimer's disease patients.…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

et al. 2007

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Amyloid precursor protein (APP) and amyloid b-peptide (Ab) have been implicated in a variety of physiological and pathological processes underlying nervous system functions. APP shares many features with adhesion molecules in that it is involved in neurite outgrowth, neuronal survival and synaptic plasticity. It is, thus, of interest to identify binding partners of APP that influence its functions. Using biochemical cross-linking techniques we have identified ATP synthase subunit a as a binding partner of the extracellular domain of APP and Ab. APP and ATP synthase colocalize at the cell surface of cultured hippocampal neurons and astrocytes. ATP synthase subunit a reaches the cell surface via the secretory pathway and is N-glycosylated during this process. Transfection of APP-deficient neuroblastoma cells with APP results in increased surface localization of ATP synthase subunit a. The extracellular domain of APP and Ab partially inhibit the extracellular generation of ATP by the ATP synthase complex. Interestingly, the binding sequence of APP and Ab is similar in structure to the ATP synthase-binding sequence of the inhibitor of F1 (IF 1 ), a naturally occurring inhibitor of the ATP synthase complex in mitochondria. In hippocampal slices, Ab and IF 1 similarly impair both short-and long-term potentiation via a mechanism that could be suppressed by blockade of GABAergic transmission. These observations indicate that APP and Ab regulate extracellular ATP levels in the brain, thus suggesting a novel mechanism in Ab-mediated Alzheimer's disease pathology.

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Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

et al. 2007

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“…Despite of these evidences, it remains unclear whether the mitochondrial dysfunction responsible of increased ROS production in AD could be a previous step to the Aβ plaques accumulation. In this regard, some studies describe ROS production as an early event before the plaques appearance that could induce the Aβ accumulation (Caspersen et al, 2005;Manczak et al, 2006;Yao et al, 2007;Karuppagounder et al, 2009). …”

Section: In Alzheimer´s Diseasementioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

144

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For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

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“…Dysfunctional mitochondria produce high levels of reactive oxygen species (ROS); these ROS can negatively affect specific mitochondrial components, including mitochondrial DNA (mtDNA), membrane lipids, and oxidative phosphorylation proteins [18,19]. For example dysregulation of complex I has been correlated with tau toxicity, and dysregulation of complex IV has been associated with increased Aβ load [20][21][22]. Additionally, specific proteins are affected by mitochondrial dysfunction in AD, including amyloid precursor protein, presenilin 1 and presenilin 2, which reside along the mitochondria-associated endoplasmic reticulum membranes [23].…”

Section: Introductionmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease

Cited by 684 publications

References 74 publications

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

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