A novel missense variant in ACAA1 contributes to early-onset Alzheimer\u2019s disease, impairs lysosomal function, and facilitates amyloid-\u03b2 pathology and cognitive decline

Rongcan Luo,Rui Bi,Liwen Tan,Xiaoqian Ran,Yu Li,Chen Zhang,Deng-Feng Zhang,Xiao Li,Kun Guo,Min Xu,Hong-Yan Jiang,Yu Fan,Lu-Xiu Yang,Yong-Gang Yao,Jing Yang,Nengyin Sheng,Maosen Ye

doi:10.1038/s41392-021-00748-4

Abstract

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.

Highlights

Alzheimer’s disease (AD, MIM: 104300) is a devastating neurodegenerative disease that afflicts a large portion of the aged population at an ever increasing rate
No pathogenic mutations in the three AD-causal genes APP, PSEN1, and PSEN2 or other neurodegenerative disorder-causal genes were observed in the AD proband or in other individuals of this family (Supplementaty Table S1)
We identified 1219 differentially expressed genes (DEGs; Padjust < 0.05) between the acyltransferase 1 (ACAA1) p.N299S and ACAA1 wild-type ACAA1 (WT) groups that were shared by both the human microglia (HM) and U251APP cells, of which 734 genes were upregulated and 485 were downregulated (Supplementaty Fig. S2c)

Summary

Introduction

Alzheimer’s disease (AD, MIM: 104300) is a devastating neurodegenerative disease that afflicts a large portion of the aged population at an ever increasing rate. Most of the pathogenic mutations of these causal genes presented in an autosomal-dominant manner and only occurred in a low proportion of (

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Conclusion