Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction.

IF 14.7 1区医学 Q1 NEUROSCIENCES

Neuron Pub Date : 2025-03-19 Epub Date: 2025-01-31 DOI:10.1016/j.neuron.2025.01.006

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

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引用次数: 0

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.

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来源期刊

Neuron 医学-神经科学

CiteScore

24.50

自引率

3.10%

发文量

382

审稿时长

1 months

期刊介绍： Established as a highly influential journal in neuroscience, Neuron is widely relied upon in the field. The editors adopt interdisciplinary strategies, integrating biophysical, cellular, developmental, and molecular approaches alongside a systems approach to sensory, motor, and higher-order cognitive functions. Serving as a premier intellectual forum, Neuron holds a prominent position in the entire neuroscience community.