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载脂蛋白 E4/4 与阿尔茨海默病小胶质细胞中的脂滴损伤有关。

APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.

机构信息

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.

出版信息

Nature. 2024 Apr;628(8006):154-161. doi: 10.1038/s41586-024-07185-7. Epub 2024 Mar 13.

DOI:10.1038/s41586-024-07185-7
PMID:38480892
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10990924/
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 cells. 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.

摘要

几种阿尔茨海默病的遗传风险因素涉及参与脂代谢的基因，其中许多脂代谢基因在神经胶质细胞中高度表达。然而，神经胶质细胞中的脂代谢与阿尔茨海默病病理之间的关系仍知之甚少。通过对阿尔茨海默病脑组织的单细胞 RNA 测序，我们鉴定出一种由脂滴相关酶 ACSL1 表达定义的小胶质细胞状态，具有 ACSL1 阳性的小胶质细胞在携带 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以 APOE 依赖性方式导致 Tau 磷酸化和神经毒性。我们的发现表明，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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/6749a09f55a7/41586_2024_7185_Fig12_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/e4274207fe04/41586_2024_7185_Fig6_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/d7b10bd13751/41586_2024_7185_Fig9_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/6749a09f55a7/41586_2024_7185_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/2162234ee9cb/41586_2024_7185_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/bc85c25659ec/41586_2024_7185_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/0638fe40f653/41586_2024_7185_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/4906a6958a50/41586_2024_7185_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/8f0f846ffef4/41586_2024_7185_Fig5_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/e4274207fe04/41586_2024_7185_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/6ea8670c002f/41586_2024_7185_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/1cb37f16e9af/41586_2024_7185_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/d7b10bd13751/41586_2024_7185_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/43f4bf888a09/41586_2024_7185_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/146040236673/41586_2024_7185_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f0e/10990924/6749a09f55a7/41586_2024_7185_Fig12_ESM.jpg

相似文献

[1]
APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.

Nature. 2024-4

[2]
APOE4/4 is linked to damaging lipid droplets in Alzheimer's microglia.

bioRxiv. 2023-7-25

[3]
APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types.

Neuron. 2018-5-31

[4]
Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer's disease.

Nat Immunol. 2023-11

[5]
Association between abnormal lipid metabolism and Alzheimer's disease: New research has revealed significant findings on the APOE4 genotype in microglia.

Biosci Trends. 2024-6-6

[6]
Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition.

J Neuroinflammation. 2014-6-19

[7]
Linking APOE4/4 genotype to microglial lipid droplets and neurotoxicity in Alzheimer's disease.

Transl Neurodegener. 2024-7-30

[8]
Differential Signaling Mediated by ApoE2, ApoE3, and ApoE4 in Human Neurons Parallels Alzheimer's Disease Risk.

J Neurosci. 2019-7-22

[9]
Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models.

Elife. 2020-6-8

[10]
APOE4 genotype and aging impair injury-induced microglial behavior in brain slices, including toward Aβ, through P2RY12.

Mol Neurodegener. 2024-3-11

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[2]
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Front Immunol. 2025-8-20

[3]
PICALM Alzheimer's risk allele causes aberrant lipid droplets in microglia.

Nature. 2025-9-3

[4]
genotypes differentially remodel the astrocytic lipid droplet-associated proteome to shape lipid droplet dynamics.

bioRxiv. 2025-8-20

[5]
MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer's disease model.

Mol Neurodegener. 2025-8-28

[6]
Lipid-Laden Microglia: Characterization and Roles in Diseases.

Cells. 2025-8-19

[7]
Functional hydrogel for modulating lipid droplets and neuroinflammation in head injury.

Adv Funct Mater. 2025-7-4

[8]
Spatiotemporal Dynamics of Central Nervous System Diseases: Advancing Translational Neuropathology via Single-Cell and Spatial Multiomics.

MedComm (2020). 2025-8-19

[9]
Glial Cells and Aging: From the CNS to the Cerebellum.

Int J Mol Sci. 2025-8-5

[10]
Induced Microglial-like Cells Derived from Familial and Sporadic Alzheimer's Disease Peripheral Blood Monocytes Show Abnormal Phagocytosis and Inflammatory Response to PSEN1 E280A Cholinergic-like Neurons.

Int J Mol Sci. 2025-7-24

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