PICALM阿尔茨海默病风险等位基因导致小胶质细胞异常脂滴，这一成果由美国芝加哥大学Jubao Duan研究团队经过不懈努力而取得。相关论文于2025年9月3日发表在《自然》杂志上。

他们的方法是鉴定显示等位基因特异性开放染色质的功能性GWAS风险变异，小组系统地鉴定了人类诱导多能干细胞（iPS）来源的神经元、星形胶质细胞和小胶质细胞中假定的LOAD风险变异，并将PICALM LOAD风险等位基因与PICALM在脂质液粒（LD）积累中的小胶质特异性作用联系起来。等位基因特异性的开放染色质图谱揭示了26个LOAD风险位点的功能风险变异，主要针对小胶质细胞。在小胶质细胞特异性PICALM位点，单核苷酸多态性rs10792832的LOAD风险等位基因降低了转录因子（PU.1）的结合和PICALM的表达，损害了β淀粉样蛋白（Aβ）和髓鞘碎片的摄取。

值得注意的是，携带PICALM风险等位基因的小胶质细胞显示胆固醇合成和LD形成途径的转录富集。小胶质细胞的遗传和药理学扰动进一步确立了PICALM表达减少、LD积累和吞噬缺陷之间的因果联系。他们的工作阐明了PICALM部位的小胶质细胞通过有害LD积累的选择性LOAD易感性，为开发临床干预措施提供了神经生物学基础。

据了解，尽管迟发性阿尔茨海默病（LOAD）的全基因组关联研究（GWAS）已经确定了许多遗传风险位点，但潜在的疾病机制在很大程度上仍不清楚。确定致病变异及其LOAD相关的细胞表型一直是一个挑战。

附：英文原文

Title: PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia

Author: Kozlova, Alena, Zhang, Siwei, Sudwarts, Ari, Zhang, Hanwen, Smirnou, Stanislau, Byeon, Seul Kee, Thapa, Christina, Sun, Xiaotong, Stephenson, Kimberley, Zhao, Xiaojie, Jamison, Brendan, Ponnusamy, Moorthi, He, Xin, Schneider, Julie A., Pandey, Akhilesh, Bennett, David A., Pang, Zhiping P., Sanders, Alan R., Bellen, Hugo J., Thinakaran, Gopal, Duan, Jubao

Issue&Volume: 2025-09-03

Abstract: Despite genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (LOAD) having identified many genetic risk loci1,2,3, the underlying disease mechanisms remain largely unclear. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Here, using our approach for identifying functional GWAS risk variants showing allele-specific open chromatin, we systematically identified putative causal LOAD-risk variants in human induced pluripotent stem (iPS)-cell-derived neurons, astrocytes and microglia, and linked a PICALM LOAD-risk allele to a microglial-specific role of PICALM in lipid droplet (LD) accumulation. Allele-specific open-chromatin mapping revealed functional risk variants for 26 LOAD-risk loci, mostly specific to microglia. At the microglial-specific PICALM locus, the LOAD-risk allele of the single-nucleotide polymorphism rs10792832 reduced transcription factor (PU.1) binding and PICALM expression, impairing the uptake of amyloid beta (Aβ) and myelin debris. Notably, microglia carrying the PICALM risk allele showed transcriptional enrichment of pathways for cholesterol synthesis and LD formation. Genetic and pharmacological perturbations of microglia further established a causal link between reduced PICALM expression, LD accumulation and phagocytosis deficits. Our work elucidates the selective LOAD vulnerability in microglia at the PICALM locus through detrimental LD accumulation, providing a neurobiological basis that can be exploited for developing clinical interventions.

DOI: 10.1038/s41586-025-09486-x

Source: https://www.nature.com/articles/s41586-025-09486-x