The Alzheimer risk factor CD2AP causes dysfunction of the brain vascular network

Milène Vandal; Ádám Institóris; Ben Korin; Colin Gunn; Suzie Lee; Ji Yeon Lee; Philippe Bourassa; Ramesh C. Mishra; Govind Peringod; Yulan Jiang; Sotaro Hirai; Camille Belzil; Louise Réveret; Cyntia Tremblay; Mada Hashem; Esteban E. Elias; Bill Meilandt; Oded Foreman; Meron Roose-Girma; Daniel A. Muruve; Wilten Nicola; Jakob Körbelin; Jeff F. Dunn; Andrew P. Braun; David Alan Bennett; Grant Robert Gordon; Frédéric Calon; Andréy S. Shaw; Minh Dang Nguyen

doi:10.1101/2020.12.10.419598

NeurosciencebioRxivDec 10, 2020

Preprint

The Alzheimer risk factor CD2AP causes dysfunction of the brain vascular network

Milène Vandal iD, Ádám Institóris iD, Ben Korin iD, Colin Gunn, Suzie Lee, Ji Yeon Lee iD, Philippe Bourassa, Ramesh C. Mishra iD, Govind Peringod iD, Yulan Jiang iD, Sotaro Hirai, Camille Belzil, Louise Réveret, Cyntia Tremblay iD, Mada Hashem iD, Esteban E. Elias, Bill Meilandt, Oded Foreman iD, Meron Roose-Girma iD, Daniel A. Muruve iD, Wilten Nicola iD, Jakob Körbelin iD, Jeff F. Dunn iD, Andrew P. Braun iD, David Alan Bennett iD, , Minh Dang Nguyen iD

Abstract

Genetic variations in CD2-associated protein (CD2AP) predispose to Alzheimers 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 A{beta} 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.

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