Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction.
1. Neuron. 2025 Mar 19;113(6):876-895.e11. doi: 10.1016/j.neuron.2025.01.006. Epub 2025 Jan 31. Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction. Vandal M(1), Institoris A(2), Reveret L(3), Korin B(4), Gunn C(1), Hirai S(1), Jiang Y(1), Lee S(1), Lee J(4), Bourassa P(3), Mishra RC(2), Peringod G(2), Arellano F(1), Belzil C(1), Tremblay C(5), Hashem M(6), Gorzo K(2), Elias E(7), Yao J(2), Meilandt B(4), Foreman O(4), Roose-Girma M(4), Shin S(2), Muruve D(7), Nicola W(8), Körbelin J(9), Dunn JF(10), Chen W(2), Park SK(11), Braun AP(2), Bennett DA(12), Gordon GRJ(2), Calon F(13), Shaw AS(14), Nguyen MD(15). Author information: (1)Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1 Canada. (2)Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary AB T2N 4N1, Canada. (3)Faculté de pharmacie, Université Laval, Québec, QC G1V 0A6, Canada; Centre de Hospitalier Universitaire de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada. (4)Department of Research Biology, Genentech, South San Francisco, CA 94080, USA. (5)Centre de Hospitalier Universitaire de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada. (6)Department of Radiology, Hotchkiss Brain Institute, University of Calgary, Calgary AB T2N 4N1, Canada. (7)Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada. (8)Departments of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary AB T2N 4N1, Canada. (9)Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany. (10)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; Department of Radiology, Hotchkiss Brain Institute, University of Calgary, Calgary AB T2N 4N1, Canada. (11)Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea. (12)Rush Alzheimer's disease Center, Rush University Medical Center, Chicago, IL 60612, USA. (13)Faculté de pharmacie, Université Laval, Québec, QC G1V 0A6, Canada; Centre de Hospitalier Universitaire de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada. Electronic address: frederic.calon@crchudequebec.ulaval.ca. (14)Department of Research Biology, Genentech, South San Francisco, CA 94080, USA. Electronic address: shaw.andrey@gene.com. (15)Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1 Canada. Electronic address: mdnguyen@ucalgary.ca. 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. Copyright © 2025 Elsevier Inc. All rights reserved. DOI: 10.1016/j.neuron.2025.01.006 PMID: 39892386 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests The authors declare no competing interests.