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Amyloid-β protein precursor modulates mitophagy and mitochondrial function through its cellular localization

delete2025-07-17
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PRE
AI
T
Taylor A. Strope
B
Benjamin Troutwine
B
Brittany M Hauger
K
Keith P. Smith
R
Russell H. Swerdlow
H
Heather Wilkins
DOI：10.1177/13872877251360243delete
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Abstract

Abstract

En 中文
<jats:sec> <jats:title>Background</jats:title> <jats:p>Amyloid-β (Aβ) is generated from amyloid-β protein precursor (AβPP) via secretase enzymes. While AβPP processing and its localization are well understood, the function of AβPP is largely unknown. AβPP has been shown to localize to mitochondria, but the consequence of this is not understood.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective</jats:title> <jats:p>We examined the consequences of modulating mitochondrial AβPP content on mitochondrial function.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>We measured mitochondrial AβPP localization in postmortem human brain from non-demented and AD subjects. To understand the effects of mitochondrial localization of AβPP on mitochondria, we leveraged AβPP constructs with increased (D23A) or decreased (3 M) mitochondrial localization compared to a wild-type (WT) construct. We measured mitochondrial function including dynamics and mitophagy.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>We observed increased AβPP mitochondrial localization in postmortem brain of sporadic AD subjects. Increased or decreased mitochondrial AβPP content led to reduced electron transport chain (ETC) activities, reduced ATP levels, increased mitochondrial superoxide production, hyperpolarized mitochondrial membrane potential, and increased mitochondrial calcium content. Reduced mitochondrial AβPP content reduced mitophagy flux, while increased mitochondrial AβPP content increased mitophagy flux. Increased or decreased mitochondrial AβPP content reduced mitochondrial biogenesis. We identified interactions between AβPP and mitophagy/autophagy proteins. We next examined if a specific motif in AβPP was responsible for alterations in mitochondrial function and mitophagy. Mitophagy flux was inhibited with expression of ΔCT AβPP, suggesting a role for the C-terminus of AβPP in mitophagy induction.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Overall, these findings highlight a critical role of AβPP in mitochondrial physiology. Alterations to AβPP mitochondrial content can lead to mitochondrial dysfunction.</jats:p> </jats:sec>
Keywords:
Amyloid-β protein precursor
Mitochondrial function
Mitophagy
Electron transport chain
Alzheimer's disease

Journal

Journal of Alzheimer's Disease cover
Journal of Alzheimer's Disease
IF:
3.1
Papers:
1.1W
Citations:
3.7W

Organization

No organization information available