LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4.
LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4.
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DOI：
10.1172/jci.insight.163822
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发表时间：
2023-04-10
期刊：
影响因子：
8
通讯作者：
Kanekiyo, Takahisa
中科院分区：
文献类型：
--
作者：
Oue, Hiroshi;Yamazaki, Yu;Qiao, Wenhui;Yuanxin, Chen;Ren, Yingxue;Kurti, Aishe;Shue, Francis;Parsons, Tammee M.;Perkerson, Ralph B.;Kawatani, Keiji;Wang, Ni;Starling, Skylar C.;Roy, Bhaskar;Mosneag, Ioana-Emilia;Aikawa, Tomonori;Holm, Marie-Louise;Liu, Chia-Chen;Inoue, Yasuteru;Sullivan, Patrick M.;Asmann, Yan W.;Kim, Betty Y. S.;Bu, Guojun;Kanekiyo, Takahisa
脑血管系统在维持脑内环境稳定方面至关重要;其失调常常导致衰老过程中的血管性认知障碍和痴呆（VCID）。VCID是老年痴呆症的第二大流行原因，仅次于阿尔茨海默病（AD），VCID和AD经常同时发生。虽然AD和VCID的发病机制涉及多种因素，但APOE 4增加了这两种疾病的风险。一种主要的载脂蛋白E（apoE）受体，低密度脂蛋白受体相关蛋白1（LRP 1），在血管壁细胞（周细胞和平滑肌细胞）中大量表达。在这里，我们研究了血管壁细胞LRP 1的缺乏如何影响脑血管系统和认知能力，使用血管壁细胞特异性Lrp 1-KO小鼠（smLrp 1-/-）在人类APOE 3或APOE 4背景。我们发现，与其各自的同窝对照小鼠相比，13至16个月大的APOE 4 smLrp 1-/-小鼠的空间记忆受损，但APOE 3 smLrp 1-/-小鼠的空间记忆没有受损。APOE 4 smLrp 1-/-小鼠中的这些破坏伴随着过度的血管旁胶质细胞活化和脑血管胶原IV减少。此外，APOE 4 smLrp 1-/-小鼠的血脑屏障（BBB）完整性被破坏。总之，我们的研究结果表明，血管壁细胞LRP 1调节血管的完整性和功能的载脂蛋白E基因型依赖的方式。
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.
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