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

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 in AD is associated with cognitive decline and genetic downregulation of CD2AP in brain microvessels impairs memory function in two distinct mouse models. The memory deficits are linked to reduced cerebral blood flow during resting state and altered neurovascular coupling in pial vessels, arterioles and capillaries. In brain endothelial cells, CD2AP regulates the levels and signaling of ApoE receptor 2 (ApoER2). Activation of the CD2AP-ApoER2 pathway with Reelin glycoprotein mitigates the toxic effects of Aβ on capillary blood flow and on vasomotion of arterioles depleted of CD2AP. We propose that deregulation of CD2AP perturbs distinct segments of the brain vascular network, and harnessing the biology of specific brain vessel types may offer refined therapeutic strategies for the treatment of AD.