普渡大学Gaurav Chopra研究组的最新研究提出了淀粉样蛋白-β通过DGAT2酶诱导脂滴介导的小胶质细胞功能障碍。该项研究成果发表在2025年5月19日出版的《免疫学》上。

小组发现，在淀粉样蛋白-β (Aβ)暴露后，小胶质细胞形成脂滴（LD），并且在AD患者和5xFAD motheme模型中，LD负荷随着与淀粉样蛋白斑块的接近而增加。负载LD的小胶质细胞表现出a β吞噬缺陷，无偏倚脂质组学分析发现，游离脂肪酸（FFAs）的减少和三酰甘油（TGs）的增加是LD形成的关键代谢转变。二酰基甘油O-酰基转移酶2 (DGAT2) -一种将FFAs转化为TGs的关键酶-促进小胶质细胞LD形成，并在motheme 5xFAD和人AD脑中增加。药理学上靶向DGAT2可改善5xFAD小鼠小胶质细胞对Aβ的摄取，减少斑块负荷和神经元损伤。这些发现确定了一种脂质介导的小胶质细胞功能障碍机制，可能成为阿尔茨海默病的治疗靶点。

据了解，小胶质细胞吞噬基因与阿尔茨海默病（AD）风险增加有关，但将遗传关联转化为细胞功能障碍的机制尚不清楚。

附：英文原文

Title: Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease

Author: Priya Prakash, Palak Manchanda, Evi Paouri, Kanchan Bisht, Kaushik Sharma, Jitika Rajpoot, Victoria Wendt, Ahad Hossain, Prageeth R. Wijewardhane, Caitlin E. Randolph, Yihao Chen, Sarah Stanko, Nadia Gasmi, Anxhela Gjojdeshi, Sophie Card, Jonathan Fine, Krupal P. Jethava, Matthew G. Clark, Bin Dong, Seohee Ma, Alexis Crockett, Elizabeth A. Thayer, Marlo Nicolas, Ryann Davis, Dhruv Hardikar, Daniela Allende, Richard A. Prayson, Chi Zhang, Dimitrios Davalos, Gaurav Chopra

Issue&Volume: 2025-05-19

Abstract: Microglial phagocytosis genes have been linked to increased risk for Alzheimer’s disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, we showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a parallel decrease in free fatty acids (FFAs) and increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. Diacylglycerol O-acyltransferase 2 (DGAT2)—a key enzyme that converts FFAs to TGs—promoted microglial LD formation and was increased in mouse 5xFAD and human AD brains. Pharmacologically targeting DGAT2 improved microglial uptake of Aβ and reduced plaque load and neuronal damage in 5xFAD mice. These findings identify a lipid-mediated mechanism underlying microglial dysfunction that could become a therapeutic target for AD.

DOI: 10.1016/j.immuni.2025.04.029

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00192-X