Brain mitovesicles undergo stage-specific remodelling during the progression of amyloid-β pathology

Forebrain mitovesicles from AppKI mice undergo stage-specific proteomic remodelling across amyloid-β pathology, with symptomatic 12-month animals forming the most molecularly distinct group.

• Why it matters: Mitochondrial dysfunction changes nonlinearly during Alzheimer’s progression, but how it appears in mitochondrial material released by brain cells is unclear.
• What they did: Forebrain-derived small extracellular vesicles and mitovesicles were isolated from wild-type and AppKI mice at 2-month presymptomatic and 12-month symptomatic stages using high-resolution density gradient fractionation, then profiled by quantitative proteomics and mitovesicle extracellular flux respiration.
• The result: At 2 months, AppKI mitovesicles showed reduced mitochondrial protein representation (including fatty acid β-oxidation and lipid-metabolism proteins) without detectable respiratory impairment; at 12 months, cargo shifted toward oxidative phosphorylation yet Complex IV-linked respiration was reduced, and a conserved 62-protein human–mouse mitovesicle core with 25 enriched disease proteins was identified.

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