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Mitochondrial Membrane Potential Influences Aβ Production and Amyloid Precursor Protein localization


 Beta amyloid (Aβ), which derives from the amyloid precursor protein (APP), forms plaques and serves as a fluid biomarker in Alzheimer’s disease (AD). How Aβ forms from APP is known, but questions relating to APP and Aβ biology remain unanswered. AD patients show mitochondrial dysfunction and an Aβ/ APP/ mitochondria relationship exists. Here, we considered how mitochondrial biology may impact APP and Aβ biology. We showed that mitochondrial depolarization routes APP to, while hyperpolarization routes APP away from, the organelle. Mitochondrial APP and cell Aβ secretion inversely correlate, as cells with more mitochondrial APP secrete less Aβ, and cells with less mitochondrial APP secrete more Aβ. Overall, our findings indicate mitochondrial function alters APP localization and suggest enhanced mitochondrial activity or factors associated with enhanced mitochondrial activity promote Aβ secretion while depressed mitochondrial activity or factors associated with depressed mitochondrial activity minimize Aβ secretion. Our data complement other studies that indicate a mitochondrial, APP, and Aβ nexus, and could help explain why cerebrospinal fluid Aβ is lower in those with AD. Our data further suggest Aβ secretion could serve as a biomarker of cell or tissue mitochondrial function.