Alzheimer's disease (AD) is characterized by synaptic failure, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive function. Pathogenic mutations in known AD causal genes such as APP, PSEN1 and PSEN2 impair a variety of pathways including protein processing, axonal transport, and metabolic homeostasis. Here, we identified a missense variant rs117916664 (c.896T>C, p.Asn299Ser [p.N299S]) of the acetyl-CoA acyltransferase 1 (ACAA1) gene in a Han Chinese AD family by whole genome sequencing, and validated its association with early-onset familial AD in an independent cohort. Further in vitro and in vivo evidence showed that ACAA1 p.N299S contributes to AD by disturbing its enzymatic activity, impairing lysosomal function, and aggravating the AB pathology and neuronal loss, which finally caused cognitive impairment in a murine model. Our findings reveal a fundamental role of peroxisome-mediated lysosomal dysfunction in AD pathogenesis.
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Submitter: Luo Rongcan / luorongcan@mail.kiz.ac.cn
Organization: Kunming Institute of Zoology, Chinese Academy of Sciences
Submission date: 2021-06-24
Aspera Command Line
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HRA000978.xlsx