Deregulation of brain endothelial CD2AP in Alzheimer's disease impairs Reelin-mediated neurovascular coupling
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.