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Updated: Mar 26, 2026
Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils
Published on: September 28, 2019
Methionine sulfoxide reductase A affects β-amyloid solubility and mitochondrial function in a mouse model of
Jackob Moskovitz1, Fang Du2, Connor F Bowman2
1Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas moskovij@ku.edu.
Abstract:
Accumulation of oxidized proteins, and especially β-amyloid (Aβ), is thought to be one of the common causes of Alzheimer's disease (AD). The current studies determine the effect of an in vivo methionine sulfoxidation of Aβ through ablation of the methionine sulfoxide reductase A (MsrA) in a mouse model of AD, a mouse that overexpresses amyloid precursor protein (APP) and Aβ in neurons. Lack of MsrA fosters the formation of methionine sulfoxide in proteins, and thus its ablation in the AD-mouse model will increase the formation of methionine sulfoxide in Aβ. Indeed, the novel MsrA-deficient APP mice (APP(+)/MsrAKO) exhibited higher levels of soluble Aβ in brain compared with APP(+) mice. Furthermore, mitochondrial respiration and the activity of cytochrome c oxidase were compromised in the APP(+)/MsrAKO compared with control mice. These results suggest that lower MsrA activity modifies Aβ solubility properties and causes mitochondrial dysfunction, and augmenting its activity may be beneficial in delaying AD progression.
Insights
Reduced methionine sulfoxide reductase A (MsrA) activity increases soluble amyloid-beta (Aβ) and impairs mitochondrial function in Alzheimer
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Oxidized proteins, particularly amyloid-beta (Aβ), are implicated in Alzheimer's disease (AD) pathogenesis.
- Methionine sulfoxide reductase A (MsrA) plays a role in repairing oxidized proteins.
Purpose of the Study:
- To investigate the in vivo effect of methionine sulfoxidation on Aβ in an AD mouse model.
- To determine the impact of ablating MsrA on Aβ accumulation and mitochondrial function.
Main Methods:
- Utilized a mouse model overexpressing amyloid precursor protein (APP) and Aβ.
- Generated MsrA-deficient APP mice (APP(+)/MsrAKO) to study methionine sulfoxidation.
- Assessed soluble Aβ levels and mitochondrial respiration.
Main Results:
- APP(+)/MsrAKO mice showed increased soluble Aβ in the brain compared to APP(+) mice.
- Mitochondrial respiration and cytochrome c oxidase activity were reduced in APP(+)/MsrAKO mice.
- Lack of MsrA activity enhanced methionine sulfoxide formation in Aβ.
Conclusions:
- Lower MsrA activity alters Aβ solubility and leads to mitochondrial dysfunction.
- Augmenting MsrA activity may offer a therapeutic strategy for delaying AD progression.
