Journal Article

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

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

2023

Overview

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.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Aged / Alzheimer Disease - pathology / Alzheimer's disease / Animals / Apolipoprotein E / Apolipoprotein E3 - metabolism / Apolipoprotein E4 / Apolipoprotein E4 - genetics / Apolipoproteins / Apolipoproteins E - metabolism / Atherosclerosis / Behavior / Blood-brain barrier / Blood-Brain Barrier - metabolism / Cerebrovascular system / Cognitive ability / Collagen (type IV) / Dementia / Dementia disorders / Females / Fibroblasts / Genotype & phenotype / Genotypes / Geriatrics / Homeostasis / Humans / Infant / Kinases / Low Density Lipoprotein Receptor-Related Protein-1 - metabolism / Low density lipoprotein receptors / Memory / Mice / Neurodegenerative diseases / Neuroscience / Pathogenesis / Pericytes / Proteins / Receptor density / Smooth muscle / Spatial memory / Vascular dementia