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Amyloid Precursor Protein Modulates Mitochondrial Function and Mitophagy
Strope, Taylor Ann
Strope, Taylor Ann
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Abstract
Abnormal accumulation of intraneuronal neurofibrillary tangles and amyloid plaques within the
brain are pathological hallmarks of Alzheimer’s disease (AD). Amyloid plaques are insoluble
extracellular aggregates of amyloid-β (Aβ). Aβ is a peptide generated from the cleavage of
amyloid precursor protein (APP) via secretase enzymes. APP is a ubiquitously expressed protein,
found at high levels within the central nervous system. Previous studies have shown APP to
localize to the mitochondria. We observed increased APP mitochondrial localization in
postmortem brain of sporadic AD subjects.
While APP processing and localization are well understood, the physiological function of
APP and the consequence of its mitochondrial localization are largely unknown. The focus of
these studies was to investigate the relationship between mitochondrial function and APP. We
used mutations in APP that alter its mitochondrial localization. We leveraged APP constructs and
mutations with increased (D23A) or decreased (3M) mitochondrial localization compared to a
wild-type (WT) construct. This allowed us to examine the relationship between APP
mitochondrial localization and mitochondrial function. We also examined the effects of APP
knockdown (missing one allele), APP knockout (missing two alleles), and APP duplication on
mitochondrial function.
Increased or decreased mitochondrial APP content in SH-SY5Y neuroblastoma cell
models led to reduced electron transport (ETC) activities, reduced ATP levels, increased
mitochondrial superoxide production, hyperpolarized mitochondrial membrane potential, and
increased mitochondrial calcium content. All of which indicate mitochondrial dysfunction.
Reduced mitochondrial APP content in SH-SY5Y cells also reduced mitophagy flux and
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mitochondrial biogenesis. However, increased mitochondrial APP content increased mitophagy
flux, but reduced mitochondrial biogenesis.
iPSC derived neurons and astrocytes exhibited similar relationships between
mitochondrial function and altered APP mitochondrial content. iPSC models with reduced
mitochondrial APP localization had reduced Aβ production and mitophagy levels but increased
mitochondrial biogenesis. Models with increased localization exhibited opposite results with
increased Aβ production and mitophagy levels but decreased mitochondrial biogenesis.
However, mitochondrial respiratory function and COX Vmax were reduced with both increased
and decreased mitochondrial APP content.
Finally, we examined the effects of APP knockout (APP KO) on mitochondrial function
in vivo. We leveraged APP KO mice to examine brain mitochondrial function and cognition.
Learning, memory, brain mitochondrial function, and mitochondrial mass were all reduced
compared in APP KO mice. Overall, these findings highlight the function of APP in
mitochondrial and bioenergetic physiology. Altered APP mitochondrial content can lead to
mitochondrial dysfunction, a hallmark observed in AD.
Description
Date
2025-01-01
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University of Kansas
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This item contains archived web content.
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Strope_ku_0099D_20256.pdf
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- Embargoed until 2176-05-31
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Keywords
Molecular biology, Biochemistry, Alzheimer's Disease, Amyloid Precursor Protein, Electron Transport Chain, Mitochondria, Mitophagy