美国斯坦福大学Tony Wyss-Coray研究组发现，APOE4/4与阿尔茨海默病小胶质细胞中的损伤性脂滴有关。相关论文于2024年3月13日在线发表在《自然》杂志上。

通过对阿尔茨海默氏症患者脑组织的单核RNA测序，研究人员发现了一种由脂滴相关酶ACSL1的表达所定义的小胶质细胞状态，在具有APOE4/4基因型的阿尔茨海默氏症患者中，ACSL1阳性的小胶质细胞最为丰富。在人类诱导多能干细胞衍生的小胶质细胞中，纤维Aβ以APOE依赖性方式诱导ACSL1表达、甘油三酯合成和脂滴积累。此外，来自含脂滴小胶质细胞的条件培养基会以APOE依赖性方式导致Tau磷酸化和神经毒性。

这些研究结果表明，阿尔茨海默病的遗传风险因素与小胶质细胞脂滴积累和神经毒性小胶质细胞衍生因子之间存在联系，这有可能为阿尔茨海默病提供治疗策略。

研究人员表示，阿尔茨海默病的几个遗传风险因素与脂质代谢基因有关，其中许多脂质基因在神经胶质细胞中高度表达。然而，人们对神经胶质细胞的脂质代谢与阿尔茨海默病病理之间的关系仍然知之甚少。

附：英文原文

Title: APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia

Author: Haney, Michael S., Plovics, Rbert, Munson, Christy Nicole, Long, Chris, Johansson, Patrik K., Yip, Oscar, Dong, Wentao, Rawat, Eshaan, West, Elizabeth, Schlachetzki, Johannes C. M., Tsai, Andy, Guldner, Ian Hunter, Lamichhane, Bhawika S., Smith, Amanda, Schaum, Nicholas, Calcuttawala, Kruti, Shin, Andrew, Wang, Yung-Hua, Wang, Chengzhong, Koutsodendris, Nicole, Serrano, Geidy E., Beach, Thomas G., Reiman, Eric M., Glass, Christopher K., Abu-Remaileh, Monther, Enejder, Annika, Huang, Yadong, Wyss-Coray, Tony

Issue&Volume: 2024-03-13

Abstract: Several genetic risk factors for Alzheimer’s disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer’s disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer’s disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer’s disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer’s disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer’s disease.

DOI: 10.1038/s41586-024-07185-7

Source: https://www.nature.com/articles/s41586-024-07185-7