Vascular ApoE4 Impairs Behavior by Modulating Gliovascular Function

Yu Yamazaki, Chia Chen Liu, Akari Yamazaki, Francis Shue, Yuka A. Martens, Yuanxin Chen, Wenhui Qiao, Aishe Kurti, Hiroshi Oue, Yingxue Ren, Ying Li, Tomonori Aikawa, Yesesri Cherukuri, John D. Fryer, Yan W. Asmann, Betty Y.S. Kim, Takahisa Kanekiyo, Guojun Bu

Research output: Contribution to journalArticlepeer-review

Abstract

The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and multiple vascular conditions. ApoE is abundantly expressed in multiple brain cell types, including astrocytes, microglia, and vascular mural cells (VMCs). Here, we show that VMC-specific expression of apoE4 in mice impairs behavior and cerebrovascular function. Expression of either apoE3 or apoE4 in VMCs was sufficient to rescue the hypercholesterolemia and atherosclerosis phenotypes seen in Apoe knockout mice. Intriguingly, vascular expression of apoE4, but not apoE3, reduced arteriole blood flow, impaired spatial learning, and increased anxiety-like phenotypes. Single-cell RNA sequencing of vascular and glial cells revealed that apoE4 in VMCs was associated with astrocyte activation, while apoE3 was linked to angiogenic signature in pericytes. Together, our data support cell-autonomous effects of vascular apoE on brain homeostasis in an isoform-dependent manner, suggesting a critical contribution of vascular apoE to AD pathogenesis.

Original languageEnglish (US)
Pages (from-to)438-447.e6
JournalNeuron
Volume109
Issue number3
DOIs
StatePublished - Feb 3 2021

Keywords

  • APOE
  • Alzheimer's disease
  • gliovascular function
  • single-cell RNA sequencing
  • vascular mural cells

ASJC Scopus subject areas

  • Neuroscience(all)

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