A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline

作者：Rongcan Luo, Yu Fan, Jing Yang, Maosen Ye, Dengfeng Zhang, Kun Guo, Xiao Li, Rui Bi, Min Xu, Lu-Xiu Yang, Yu Li, Xiaoqian Ran, Hongyan Jiang, Chen Zhang, Liwen Tan, Nengyin Sheng, Yong‐Gang Yao · 发表于：Signal Transduction and Targeted Therapy · 年份：2021 · DOI：10.1038/s41392-021-00748-4 · 被引用次数：40 · 研究领域：Peroxisome Proliferator-Activated Receptors、Cellular transport and secretion、Alzheimer's disease research and treatments

Alzheimer's disease (AD) is characterized by progressive synaptic dysfunction, neuronal death, and brain atrophy, with amyloid-β (Aβ) 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 (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 Aβ 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.