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

Article type: Research Article

Authors: Wilkins, Heather M.^{a; b; c; *} | Troutwine, Benjamin R.^{a; b} | Menta, Blaise W.^{b; c} | Manley, Sharon J.^{a; b} | Strope, Taylor A.^{b; c} | Lysaker, Colton R.^{b; c} | Swerdlow, Russell H.^{a; b; c; d}

Affiliations: [a] Department of Neurology University of Kansas Medical Center, Kansas City, KS, USA | [b] University of Kansas Alzheimer’s Disease Center, Kansas City, KS, USA | [c] Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA | [d] Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA

Correspondence: [*] Correspondence to: Heather M. Wilkins, University of Kansas Medical Center, 3901 Rainbow Blvd MS 3030, Kansas City, KS 66160, USA. Tel.: +1 913 574 1507; E-mail: [email protected].

Abstract: Background:Amyloid-β (Aβ), which derives from the amyloid-β protein precursor (AβPP), forms plaques and serves as a fluid biomarker in Alzheimer’s disease (AD). How Aβ forms from AβPP is known, but questions relating to AβPP and Aβ biology remain unanswered. AD patients show mitochondrial dysfunction, and an Aβ/AβPP mitochondria relationship exists. Objective:We considered how mitochondrial biology may impact AβPP and Aβ biology. Methods:SH-SY5Y cells were transfected with AβPP constructs. After treatment with FCCP (uncoupler), Oligomycin (ATP synthase inhibitor), or starvation Aβ levels were measured. β-secretase (BACE1) expression was measured. Mitochondrial localized full-length AβPP 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 AβPP to, while hyperpolarization routes AβPP away from, the organelle. Mitochondrial AβPP and cell Aβ secretion inversely correlate, as cells with more mitochondrial AβPP secrete less Aβ, and cells with less mitochondrial AβPP secrete more Aβ. An inverse relationship between secreted/extracellular Aβ and intracellular Aβ was observed. Conclusion:Our findings indicate mitochondrial function alters AβPP localization and suggest enhanced mitochondrial activity promotes Aβ secretion while depressed mitochondrial activity minimizes Aβ secretion. Our data complement other studies that indicate a mitochondrial, AβPP, 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.

Keywords: Amyloid, amyloid-beta protein precursor, membrane potential, mitochondria

DOI: 10.3233/JAD-215280

Journal: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 381-394, 2022