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Updated: Oct 12, 2025
Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils
Published on: September 28, 2019
Mitochondrial Membrane Potential Influences Amyloid-β Protein Precursor Localization and Amyloid-β Secretion
Heather M Wilkins1,2,3, Benjamin R Troutwine1,2, Blaise W Menta2,3
1Department of Neurology University of Kansas Medical Center, Kansas City, KS, USA.
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.
Insights
Mitochondrial function influences amyloid-beta (Aβ) production. Enhanced mitochondrial activity promotes Aβ secretion, while depressed activity minimizes it, suggesting Aβ as a biomarker for mitochondrial health.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is linked to amyloid-beta (Aβ) plaques, derived from amyloid-beta protein precursor (AβPP).
- Mitochondrial dysfunction is observed in AD patients, suggesting a connection between mitochondria, AβPP, and Aβ.
- The precise relationship between mitochondrial biology and AβPP/Aβ metabolism remains incompletely understood.
Purpose of the Study:
- To investigate the impact of mitochondrial biology on amyloid-beta protein precursor (AβPP) and amyloid-beta (Aβ) processing.
- To explore the correlation between mitochondrial localization of AβPP and Aβ secretion.
- To determine if Aβ secretion can serve as a biomarker for cellular mitochondrial function.
Main Methods:
- Utilized SH-SY5Y cells transfected with AβPP constructs and subjected to various mitochondrial stress conditions (uncoupling, ATP synthase inhibition, starvation).
- Quantified Aβ levels, β-secretase (BACE1) expression, and mitochondrial AβPP localization.
- Verified key findings in induced pluripotent stem cell (iPSC)-derived neurons and ρ0 cells lacking mitochondrial DNA.
Main Results:
- Mitochondrial depolarization was found to direct AβPP towards the organelle, while hyperpolarization moved it away.
- An inverse correlation was observed between mitochondrial AβPP levels and Aβ secretion; higher mitochondrial AβPP correlated with lower Aβ secretion.
- A reciprocal relationship was noted between secreted/extracellular Aβ and intracellular Aβ levels.
Conclusions:
- Mitochondrial function significantly influences AβPP localization and subsequent Aβ secretion.
- Increased mitochondrial activity enhances Aβ secretion, whereas decreased activity suppresses it.
- These findings support a nexus between mitochondria, AβPP, and Aβ, potentially explaining lower cerebrospinal fluid Aβ in AD and suggesting Aβ secretion as a biomarker for mitochondrial health.
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