Mitochondrial Membrane Potential Influences Amyloid-ß Protein Precursor Localization and Amyloid-ß Secretion.

ABSTRACT

BACKGROUND: Amyloid-ß (Aß), which derives from the amyloid-ß protein precursor (AßPP), forms plaques and serves as a fluid biomarker in Alzheimer's disease (AD). How Aß forms from AßPP is known, but questions relating to AßPP and Aß biology remain unanswered. AD patients show mitochondrial dysfunction, and an Aß/AßPP mitochondria relationship exists. OBJECTIVE: We considered how mitochondrial biology may impact AßPP and Aß biology. METHODS: SH-SY5Y cells were transfected with AßPP constructs. After treatment with FCCP (uncoupler), Oligomycin (ATP synthase inhibitor), or starvation Aß levels were measured. ß-secretase (BACE1) expression was measured. Mitochondrial localized full-length AßPP was also measured. All parameters listed were measured in ρ0 cells on an SH-SY5Y background. iPSC derived neurons were also used to verify key results. RESULTS: We showed that mitochondrial depolarization routes AßPP to, while hyperpolarization routes AßPP away from, the organelle. Mitochondrial AßPP and cell Aß secretion inversely correlate, as cells with more mitochondrial AßPP secrete less Aß, and cells with less mitochondrial AßPP secrete more Aß. An inverse relationship between secreted/extracellular Aß and intracellular Aß was observed. CONCLUSION: Our findings indicate mitochondrial function alters AßPP localization and suggest enhanced mitochondrial activity promotes Aß secretion while depressed mitochondrial activity minimizes Aß secretion. Our data complement other studies that indicate a mitochondrial, AßPP, and Aß nexus, and could help explain why cerebrospinal fluid Aß is lower in those with AD. Our data further suggest Aß secretion could serve as a biomarker of cell or tissue mitochondrial function.