title: APOE genotype-dependent modulation of astrocyte chemokine CCL3 production.
abstract: Apolipoprotein E (apoE) is well known as a regulator of cholesterol homeostasis, and is increasingly recognized to play a prominent role in the modulation of innate immune response, including cell-to-cell communication and migration. Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder characterized by neuroinflammation that appears to be an important component of the pathophysiology of the disease. Astrocytes are the majority cell type in brain, exerting significant influence over a range of central nervous system activities, including microglial-mediated neuroinflammatory responses. As the resident innate immune effector cells of the brain, microglia respond to soluble chemical signals released from tissue during injury and disease by mobilizing to lesion sites, clearing toxic molecules, and releasing chemical signals of their own. While microglial-mediated neuroinflammation in the AD brain remains an area of intense investigation, the mechanisms underlying reinforcement and regulation of these aberrant microglial responses by astrocytes are largely unstudied. Moreover, although inheritance of APOE ɛ4 represents the greatest genetic risk factor for sporadic AD, the mechanism by which apoE isoforms differentially influence AD pathophysiology is unknown. Here we show that APOE ɛ4 genotype specifically modulates astrocyte secretion of potent microglial chemotactic agents, including CCL3, thus providing evidence that APOE modulation of central nervous system (CNS) innate immune response is mediated through astrocytes.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Eiron
authors.initials: E
authors.lastname: Cudaback
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000096:biosynthesis*; D005838:Genotype; D006801:Humans; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D054405:Chemokine CCL3
keywords: APOE; Alzheimer's Disease; astrocytes; chemokine; neuroinflammation
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