Defining the role of the Alzheimer disease risk factor CD2AP in brain vascular function

Abstract

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.

Therapeutic Targeting of Rab GTPases: Relevance for Alzheimer’s Disease

“…Overexpression of APP in cultured rat basal forebrain cholinergic neurons (BFCNs) leads to enlarged endosomes and selective upregulation of RIN3 [125], which may indicate a role for RIN3 in this pathology given its links to Rab5 [131]. Notably, RIN3 interacts with the AD risk factor proteins bridging integrator 1 (BIN1) [132] and CD2-associated protein (CD2AP) [133,134], recruiting them to early endosomes. RIN3 and CD2AP function together to increase toxic APP β-CTF production by disrupting BACE1 and APP trafficking [131].…”