Subcellular proteomics and iPSC modeling uncover reversible mechanisms of axonal pathology in Alzheimer's disease.

ABSTRACT: Dystrophic neurites (also termed axonal spheroids) are found around amyloid deposits in Alzheimer's disease (AD), where they impair axonal electrical conduction, disrupt neural circuits and correlate with AD severity. Despite their importance, the mechanisms underlying spheroid formation remain incompletely understood. To address this, we developed a proximity labeling approach to uncover the proteome of spheroids in human postmortem and mouse brains. Additionally, we established a human induced pluripotent stem cell (iPSC)-derived AD model enabling mechanistic investigation and optical electrophysiology. These complementary approaches revealed the subcellular molecular architecture of spheroids and identified abnormalities in key biological processes, including protein turnover, cytoskele

SUBMITTER: Cai Y 

PROVIDER: S-EPMC11922768 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature