内皮细胞CD2AP的缺失导致性别依赖性脑血管功能障碍。

Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction.

作者信息

Vandal Milène, Institoris Adam, Reveret Louise, Korin Ben, Gunn Colin, Hirai Sotaro, Jiang Yulan, Lee Sukyoung, Lee Jiyeon, Bourassa Philippe, Mishra Ramesh C, Peringod Govind, Arellano Faye, Belzil Camille, Tremblay Cyntia, Hashem Mada, Gorzo Kelsea, Elias Esteban, Yao Jinjing, Meilandt Bill, Foreman Oded, Roose-Girma Meron, Shin Steven, Muruve Daniel, Nicola Wilten, Körbelin Jakob, Dunn Jeff F, Chen Wayne, Park Sang-Ki, Braun Andrew P, Bennett David A, Gordon Grant R J, Calon Frédéric, Shaw Andrey S, Nguyen Minh Dang

机构信息

Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1 Canada.

Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary AB T2N 4N1, Canada.

出版信息

Neuron. 2025 Mar 19;113(6):876-895.e11. doi: 10.1016/j.neuron.2025.01.006. Epub 2025 Jan 31.

DOI:10.1016/j.neuron.2025.01.006

PMID:39892386

Abstract

Polymorphisms in CD2-associated protein (CD2AP) predispose to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. Here, we show that loss of CD2AP in cerebral blood vessels is associated with cognitive decline in AD subjects and that genetic downregulation of CD2AP in brain vascular endothelial cells impairs memory function in male mice. Animals with reduced brain endothelial CD2AP display altered blood flow regulation at rest and during neurovascular coupling, defects in mural cell activity, and an abnormal vascular sex-dependent response to Aβ. Antagonizing endothelin-1 receptor A signaling partly rescues the vascular impairments, but only in male mice. Treatment of CD2AP mutant mice with reelin glycoprotein that mitigates the effects of CD2AP loss function via ApoER2 increases resting cerebral blood flow and even protects male mice against the noxious effect of Aβ. Thus, endothelial CD2AP plays critical roles in cerebrovascular functions and represents a novel target for sex-specific treatment in AD.

摘要

CD2相关蛋白（CD2AP）的多态性易导致阿尔茨海默病（AD），但其潜在机制仍不清楚。在此，我们表明脑血管中CD2AP的缺失与AD患者的认知衰退相关，并且脑血管内皮细胞中CD2AP的基因下调会损害雄性小鼠的记忆功能。脑内皮CD2AP减少的动物在静息状态和神经血管耦合期间表现出血流调节改变、壁细胞活性缺陷以及对Aβ的血管性别依赖性异常反应。拮抗内皮素-1受体A信号传导可部分挽救血管损伤，但仅在雄性小鼠中有效。用通过载脂蛋白E受体2（ApoER2）减轻CD2AP功能丧失影响的Reelin糖蛋白治疗CD2AP突变小鼠，可增加静息脑血流量，甚至保护雄性小鼠免受Aβ的有害影响。因此，内皮CD2AP在脑血管功能中起关键作用，是AD性别特异性治疗的新靶点。