PT  - JOURNAL ARTICLE
AU  - Milène Vandal
AU  - Adam Institoris
AU  - Ben Korin
AU  - Colin Gunn
AU  - Suzie Lee
AU  - Jiyeon Lee
AU  - Philippe Bourassa
AU  - Ramesh C. Mishra
AU  - Govind Peringod
AU  - Yulan Jiang
AU  - Sotaro Hirai
AU  - Camille Belzil
AU  - Louise Reveret
AU  - Cyntia Tremblay
AU  - Mada Hashem
AU  - Esteban Elias
AU  - Bill Meilandt
AU  - Oded Foreman
AU  - Meron Rouse-Girma
AU  - Daniel Muruve
AU  - Wilten Nicola
AU  - Jakob Körbelin
AU  - Jeff F. Dunn
AU  - Andrew P. Braun
AU  - David A. Bennett
AU  - Grant R.J. Gordon
AU  - Frédéric Calon
AU  - Andrey S. Shaw
AU  - Minh Dang Nguyen
TI  - The Alzheimer risk factor CD2AP causes dysfunction of the brain vascular network
AID  - 10.1101/2020.12.10.419598
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2020.12.10.419598
4099  - http://biorxiv.org/content/early/2022/09/06/2020.12.10.419598.short
4100  - http://biorxiv.org/content/early/2022/09/06/2020.12.10.419598.full
AB  - Genetic variations in CD2-associated protein (CD2AP) predispose to Alzheimer’s disease (AD) but the underlying mechanisms remain unknown. Here, we show that a cerebrovascular loss of CD2AP is associated with cognitive decline in AD and that genetic downregulation of CD2AP in brain endothelial cells impairs memory function in two distinct mouse models. Mice with reduced CD2AP in brain microvessels display decreased resting cerebral blood flow, impaired functional hyperemia and vasomotion. In brain endothelial cells, CD2AP regulates the levels and signaling of ApoE receptor 2 elicited by Reelin glycoprotein. Activation of the CD2AP-ApoER2 pathway with Reelin mitigates the toxic effects of Aβ on resting blood flow and vasomotion of brain vessels depleted of CD2AP. Thus, we demonstrate that deregulation of CD2AP perturbs specific functions and segments of the cerebral microvasculature and propose that targeting CD2AP molecular partners may offer refined therapeutic strategies for the treatment of AD.Competing Interest StatementThe authors have declared no competing interest.