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Pathologic mitophagy in neurites induces mitochondrial plaques in AD mouse brains

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE245930 | GEO | 2026/06/02

REPOSITORIES: GEO

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Pathologic mitophagy in neurites induces mitochondrial plaques in AD mouse brains [XD_MPP_Hippocampus]

Project description:Dysfunctional mitophagy is considered an important component of Alzheimer's disease (AD) pathology, however, direct in vivo evidence and underlying mechanisms are lacking. Using a newly established AD mitophagy reporter mouse model (APP/PSEN1/mt-keima), we find that the basal mitophagy of neuronal soma in the hippocampal CA1 region of AD mice is selectively impaired. Pathologic mitophagy is highly activated in neurites in both the cortex and hippocampus regions of AD mice, with abnormal accumulation of mitochondria. These aberrantly accumulated mitochondria are fragmented and trigger massive formation of mitophagosomes and mitolysomes. However, the degradation of mitochondria is incomplete, likely due to inadequate maturation of lysosomal protease and de-acidification of lysosomes, leading to the mitochondrial accumulation within autophagic vacuoles. The resulting swollen neurites coalesce into structures containing mitochondria at different stages of degradation, that we term mitochondrial plaques (MPs). While MPs and Aβ plaques can emerge independently at early stages, they eventually develop into mixed MP/Aβ plaques. MPs are positive of amyloid precursor protein (APP) and contribute to over 60% of all APP detected in/around MPs, explaining the eventual development of mixed plaques. Our study identifies mitochondria as prominent constituent within autophagic vacuoles in dystrophic neurites and MPs as a promising new therapeutic target for AD. The hippocampus samples of APP/PSEN1/mt-keima and WT/mt-keima at 9, 15, 25, 30 and 50 wks were collected from 3 mice per age group per genotype group and subjected to total RNA isolation to understand what metabolism-related gene expression and pathways changes occur in AD during aging.

2026-05-29 | GSE245929 | GEO