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J Biol Chem. 2015 May 29;290(22):14208-17. doi: 10.1074/jbc.M114.625251. Epub 2015 Apr 22.

Apolipoprotein E Inhibits Cerebrovascular Pericyte Mobility through a RhoA Protein-mediated Pathway.

Author information

1
From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
2
From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224 bu.guojun@mayo.edu.
3
From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224 kanekiyo.takahisa@mayo.edu.

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.

KEYWORDS:

LRP1; Ras homolog gene family, member A (RhoA); adhesion; apolipoprotein E (ApoE); migration; pericytes; vascular biology

PMID:
25903128
PMCID:
PMC4447989
DOI:
10.1074/jbc.M114.625251
[Indexed for MEDLINE]
Free PMC Article

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