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APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia
Nature ( IF 50.5 ) Pub Date : 2024-03-13 , DOI: 10.1038/s41586-024-07185-7
Michael S Haney 1, 2 , Róbert Pálovics 1, 2 , Christy Nicole Munson 1, 2 , Chris Long 3 , Patrik K Johansson 3 , Oscar Yip 4 , Wentao Dong 5 , Eshaan Rawat 5 , Elizabeth West 6 , Johannes C M Schlachetzki 6 , Andy Tsai 1, 2 , Ian Hunter Guldner 1, 2 , Bhawika S Lamichhane 1, 2 , Amanda Smith 1, 2 , Nicholas Schaum 1, 2 , Kruti Calcuttawala 1, 2 , Andrew Shin 1, 2 , Yung-Hua Wang 4 , Chengzhong Wang 4 , Nicole Koutsodendris 4, 7 , Geidy E Serrano 8 , Thomas G Beach 9 , Eric M Reiman 9 , Christopher K Glass 7 , Monther Abu-Remaileh 5 , Annika Enejder 3 , Yadong Huang 4, 7, 10, 11 , Tony Wyss-Coray 1, 2, 12
Affiliation  

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.



中文翻译:


APOE4/4 与阿尔茨海默病小胶质细胞中脂滴的破坏有关



阿尔茨海默病的几个遗传风险因素涉及脂质代谢相关的基因,并且许多这些脂质基因在神经胶质细胞中高度表达1 。然而,神经胶质细胞的脂质代谢与阿尔茨海默病病理学之间的关系仍然知之甚少。通过对阿尔茨海默病脑组织进行单核 RNA 测序,我们发现了由脂滴相关酶 ACSL1 表达定义的小胶质细胞状态,其中 ACSL1 阳性小胶质细胞在具有APOE4/4基因型的阿尔茨海默病患者中最为丰富。 。在人诱导多能干细胞衍生的小胶质细胞中,纤维状 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,含有脂滴的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。我们的研究结果表明,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,可能为阿尔茨海默病提供治疗策略。

更新日期:2024-03-15
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