title: Apolipoprotein E Inhibits Cerebrovascular Pericyte Mobility through a RhoA Protein-mediated Pathway.
abstract: Pericytes play a critical role in the cerebrovasculature within the CNS. These small contractile cells produce large quantities of apolipoprotein E (apoE) whose isoforms influence cerebrovascular functions and determine the genetic risk for Alzheimer disease. Despite extensive studies on astrocyte-secreted apoE, which supports synapses by transporting cholesterol to neurons, the biochemical properties and function of apoE secreted by pericytes are not clear. Because pericytes mediate important functions in the CNS, including the initiation of glial scar formation, angiogenesis, and maintenance of the blood-brain barrier, we investigated the potential role of apoE in pericyte mobility. We found that knockdown of apoE expression significantly accelerates pericyte migration, an effect that can be rescued by exogenous apoE3, but not apoE4, a risk factor for Alzheimer disease. ApoE-regulated migration of pericytes also requires the function of the low-density lipoprotein receptor-related protein 1 (LRP1), a major apoE receptor in the brain that is abundantly expressed in pericytes. Because apoE-knockdown also leads to enhanced cell adhesion, we investigated the role of apoE in the regulation of the actin cytoskeleton. Interestingly, we found that the levels of active RhoA are increased significantly in apoE knockdown pericytes and that RhoA inhibitors blocked pericyte migration. Taken together, our results suggest that apoE has an intrinsic role in pericyte mobility, which is vital in maintaining cerebrovascular function. These findings provide novel insights into the role of apoE in the cerebrovascular system.
authors.affiliation: From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Casey
authors.affiliation: From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Atagi
authors.affiliation: From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Masaya
authors.initials: M
authors.lastname: Tachibana
authors.affiliation: From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224 bu.guojun@mayo.edu.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224 kanekiyo.takahisa@mayo.edu.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
mesh_terms: D000199:Actins / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism*; D001921:Brain / Q000098:blood supply; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation; D002784:Cholesterol / Q000378:metabolism; D003470:Culture Media; D017077:Culture Media, Conditioned / Q000737:chemistry; D003599:Cytoskeleton / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D020868:Gene Silencing; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000199:Actins; D001057:Apolipoproteins E; D003470:Culture Media; D017077:Culture Media, Conditioned; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D034741:RNA, Small Interfering; D002784:Cholesterol; D020742:rhoA GTP-Binding Protein
keywords: LRP1; Ras homolog gene family, member A (RhoA); adhesion; apolipoprotein E (ApoE); migration; pericytes; vascular biology