摘要
Alzheimer’s disease(AD)is characterized by progressive synaptic dysfunction,neuronal death,and brain atrophy,with amyloid-p(Ap)plaque deposits and hyperphosphorylated tau neurofibrillary tangle accumulation in the brain tissue,which all lead to loss of cognitive function.Pathogenic mutations in the well-known AD causal genes including 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(ACM1)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 Ap 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.
基金
The study was supported by the National Natural Science Foundation of China(31730037 to Y.-G.Y.,31900737 to R.L.,82022017 to D.-F.Z.)
the Strategic Priority Research Program(B)of CAS(XDB02020003 to Y.-G.Y.)
the Bureau of Frontier Sciences and Education,CAS(grant no.QYZDJ-SSW-SMC005 to Y.-G.Y.)
the Original Innovation Project"from 0 to 1"of Basic Frontier Scientific Research Program,CAS(ZDBS-LY-SM031 to R.L.)
the Yunnan Science and Technology Plan Project(202001AT070107 to R.L)
the CAS"Light of West China"Program(2020000023 to R.L.)
the Youth Innovation Promotion Association of CAS(to R.L.and D.-F.Z.)
the Training of High-Level Health Technical Personnel in Yunnan Province,Medical Academic Leader(D-2018047 to H.-Y.J.).