LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4

Hiroshi Oue, Yu Yamazaki, Wenhui Qiao, Chen Yuanxin, Yingxue Ren, Aishe Kurti, Francis Shue, Tammee M. Parsons, Ralph B. Perkerson, Keiji Kawatani, Ni Wang, Skylar C. Starling, Bhaskar Roy, Ioana Emilia Mosneag, Tomonori Aikawa, Marie Louise Holm, Chia Chen Liu, Yasuteru Inoue, Patrick M. Sullivan, Yan W. AsmannBetty Y.S. Kim, Guojun Bu, Takahisa Kanekiyo

Research output: Contribution to journalArticlepeer-review


Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer’s disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell–specific Lrp1-KO mice (smLrp1–/–) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1–/– mice but not in the APOE3 smLrp1–/– mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1–/– mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1–/– mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype–dependent manner.

Original languageEnglish (US)
Article numbere163822
JournalJCI Insight
Issue number7
StatePublished - Apr 10 2023

ASJC Scopus subject areas

  • General Medicine


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