Mitochondrial Membrane Potential Influences Amyloid-beta Protein Precursor Localization and Amyloid-beta Secretion

Background: Amyloid-beta (A beta), which derives from the amyloid-beta protein precursor (A beta PP), forms plaques and serves as a fluid biomarker in Alzheimer's disease (AD). How A beta forms from A beta PP is known, but questions relating to A beta PP and A beta biology remain unanswered. AD patients show mitochondrial dysfunction, and an A beta/A beta PP mitochondria relationship exists. Objective: We considered how mitochondrial biology may impact A beta PP and A beta biology. Methods: SH-SY5Y cells were transfected with A beta PP constructs. After treatment with FCCP (uncoupler), Oligomycin (ATP synthase inhibitor), or starvation A beta levels were measured. beta-secretase (BACE1) expression was measured. Mitochondrial localized full-length A beta PP was also measured. All parameters listed were measured in rho 0 cells on an SH-SY5Y background. iPSC derived neurons were also used to verify key results. Results: We showed that mitochondrial depolarization routes A beta PP to, while hyperpolarization routes A beta PP away from, the organelle. Mitochondrial A beta PP and cell A beta secretion inversely correlate, as cells with more mitochondrial A beta PP secrete less A beta, and cells with less mitochondrial A beta PP secrete more A beta. An inverse relationship between secreted/extracellular A beta and intracellular A beta was observed. Conclusion: Our findings indicate mitochondrial function alters A beta PP localization and suggest enhanced mitochondrial activity promotes A beta secretion while depressed mitochondrial activity minimizes A beta secretion. Our data complement other studies that indicate a mitochondrial, A beta PP, and A beta nexus, and could help explain why cerebrospinal fluid A beta is lower in those with AD. Our data further suggest A beta secretion could serve as a biomarker of cell or tissue mitochondrial function.