气候变化领域集成服务门户(CCPortal): Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

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DOI	10.1073/pnas.2102191118
	Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol
	Wang H.; Kulas J.A.; Wang C.; Holtzman D.M.; Ferris H.A.; Hansen S.B.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:33
英文摘要	Alzheimer's disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic risk factor for sporadic AD. In vitro evidence suggests that apoE links to Aβ production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with β- and γ-secretases to generate Aβpeptide. We find that the targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid clusters, where it interacts with α-secretase and gives rise to soluble APP-α (sAPP-α), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting that the ratio of Aβ to sAPP-α is regulated by the trafficking of the substrate, not the enzymes. We conclude that cholesterol is kept low in neurons, which inhibits Aβ accumulation and enables the astrocyte regulation of Aβ accumulation by cholesterol signaling. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Alzheimer's; ApoE; Cholesterol; Lipids; Neurodegeneration
语种	英语
scopus关键词	alpha secretase; amyloid beta protein; amyloid precursor protein; apolipoprotein E3; apolipoprotein E4; beta secretase; cholesterol; gamma secretase; ganglioside; monosialotetrahexosylganglioside 1; sterol regulatory element binding protein 2; tau protein; unclassified drug; amyloid beta protein; ApoE protein, human; Apoe protein, mouse; apolipoprotein E; cholesterol; isoprotein; secretase; Srebf2 protein, mouse; sterol regulatory element binding protein 2; Alzheimer disease; amyloid plaque; animal cell; animal experiment; animal model; animal tissue; Article; astrocyte; cholesterol synthesis; cholesterol transport; controlled study; embryo; lipid raft; mouse; nerve cell; nerve cell membrane; Neuro-2a cell line; nonhuman; protein processing; protein protein interaction; signal transduction; animal; astrocyte; brain; cell membrane; cytology; drug effect; gene expression regulation; genetics; HEK293 cell line; human; knockout mouse; metabolism; nerve cell; physiology; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Apolipoproteins E; Astrocytes; Brain; Cell Membrane; Cholesterol; Gene Expression Regulation; HEK293 Cells; Humans; Mice; Mice, Knockout; Neurons; Protein Isoforms; Sterol Regulatory Element Binding Protein 2
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251065
作者单位	Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, United States; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, United States; Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL 33458, United States; Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA 22908, United States; Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, United States; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University, School of Medicine, St. Louis, MO 63110, United States
推荐引用方式 GB/T 7714	Wang H.,Kulas J.A.,Wang C.,et al. Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol[J],2021,118(33).
APA	Wang H.,Kulas J.A.,Wang C.,Holtzman D.M.,Ferris H.A.,&Hansen S.B..(2021).Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol.Proceedings of the National Academy of Sciences of the United States of America,118(33).
MLA	Wang H.,et al."Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol".Proceedings of the National Academy of Sciences of the United States of America 118.33(2021).