Apolipoprotein E inhibits cerebrovascular pericyte mobility through a RhoA protein-mediated pathway

Caroline S. Casey, Yuka Atagi, Yu Yamazaki, Mitsuru Shinohara, Masaya Tachibana, Yuan Fu, Guojun D Bu, Takahisa Kanekiyo

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)14208-14217
Number of pages10
JournalJournal of Biological Chemistry
Volume290
Issue number22
DOIs
StatePublished - May 29 2015

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rhoA GTP-Binding Protein
Pericytes
Apolipoproteins E
Low Density Lipoprotein Receptor-Related Protein-1
Alzheimer Disease
Apolipoprotein E3
Apolipoprotein E4
Cell adhesion
Blood-Brain Barrier
Actin Cytoskeleton
Cell Adhesion
Neuroglia
Astrocytes
Synapses
Neurons
Cicatrix
Actins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Apolipoprotein E inhibits cerebrovascular pericyte mobility through a RhoA protein-mediated pathway. / Casey, Caroline S.; Atagi, Yuka; Yamazaki, Yu; Shinohara, Mitsuru; Tachibana, Masaya; Fu, Yuan; Bu, Guojun D; Kanekiyo, Takahisa.

In: Journal of Biological Chemistry, Vol. 290, No. 22, 29.05.2015, p. 14208-14217.

Research output: Contribution to journalArticle

Casey, Caroline S. ; Atagi, Yuka ; Yamazaki, Yu ; Shinohara, Mitsuru ; Tachibana, Masaya ; Fu, Yuan ; Bu, Guojun D ; Kanekiyo, Takahisa. / Apolipoprotein E inhibits cerebrovascular pericyte mobility through a RhoA protein-mediated pathway. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 22. pp. 14208-14217.
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