Background Brain hypoperfusion is the earliest change observed in Alzheimer’s Disease (AD) brains. Degeneration of the brain vasculature, that includes cerebral amyloid pathology, white matter hyperintensities and cortical infracts, isomnipresent in AD, and predicts the progression of cognitive decline in AD patients. CD2‐associated protein (CD2AP) functions as scaffolding protein for cytoskeletal remodeling, membrane trafficking during clathrin‐mediated receptor endocytosis and cell‐cell interactions. Interestingly, polymorphisms in CD2AP constitute one of the top 10 genetic predisposition factor to AD. Since CD2AP is enriched in brain endothelial cells (BECs) that form the brain microvessels, we reason that the protein plays a key role in BECs and therefore, defects in CD2AP may contribute to cerebrovascular dysfunction observed in AD. Method We use a multidisciplinary approach (culture of primary BECs and cerebral arteries, two‐photon brain imaging of awake active mice and analysis of isolated brain microvessels from human AD volunteers) to investigate the role of CD2AP in BECs and brain vascular function. Result We found that 1) CD2AP regulates the Apolipoprotein E receptor 2 (ApoER2) in BECs, 2) the CD2AP/ApoER2 axis is key for brain vascular function in vitro and in vivo and 3) human AD volunteers have altered the levels of CD2AP and this alteration is associated with cognitive dysfunction. Conclusion We propose that the deregulation of the ApoER2/CD2AP axis contributes to the vascular defects observed in AD.

Cerebrovascular dysfunction is increasingly recognized as a major contributor to Alzheimer’s disease (AD). CD2-associated protein (CD2AP), an important predisposing factor for the disease, is enriched in the brain endothelium but the function of protein in the brain vasculature remains undefined. Here, we report that lower levels of CD2AP in brain vessels of human AD volunteers are associated with cognitive deficits. In awake mice, we show that brain endothelial CD2AP regulates cerebral blood flow during resting state and functional hyperemia. In the endothelium, CD2AP controls the levels and signaling of apolipoprotein E receptor 2 (ApoER2), a receptor activated by Reelin glycoprotein that is linked to memory function. Further, Reelin promotes brain vessel dilation and functional hyperemia and both effects are modulated by endothelial CD2AP. Finally, lower levels of ApoER2 in brain vessels are associated with vascular defects and cognitive dysfunction in AD individuals. Thus, deregulation of CD2AP impairs neurovascular coupling and harnessing the biology of the Reelin-ApoER2-CD2AP signaling axis in the brain endothelium may improve brain vascular dysfunction in AD patients.

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