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

Abstract

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.

CD2AP is Co-Expressed with Tropomyosin-Related Kinase A and Ras-Related Protein Rab-5A in Cholinergic Neurons of the Murine Basal Forebrain

“…Therefore, this served as a convenient negative control to quantify background signals from ChAT and CD2AP antibody immunostaining. Note that, although, CD2AP signal was not present in the cell bodies of cortical CHAT-GFP neurons, it was expressed in cortical vascular structures and non-neuronal cells, as expected (Vandal et al, 2022). Taken together, these results validate the specificity of CD2AP immunostaining, and qualitatively show that CD2AP is co-expressed with ChAT in the substantia innominata (basal forebrain), vDB, and striatum.…”

“…Concurrently, CD2AP was identified as a genetic risk factor for the development of AD in humans (Hollingworth et al, 2011;Naj et al, 2011), a finding that has been supported by a substantial number of studies across model organism species, including Mus musculus (Vandal et al, 2022), Drosophila (Ojelade et al, 2019;Shulman et al, 2014), and Caenorhabditis elegans (Alvarez et al, 2022;Kim et al, 2018). Previously established Cd2ap variants have even been incorporated along with variants in Trem2 em1Adiuj , App em1Adiuj and Apoe tm1.1(APOE*4)Adiuj into a multi-genetic/causal, humanized mouse model of AD (JAX Strain# 033873) (Jung et al, 2023;Pandey et al, 2023).…”

“…Although CD2AP is known to be expressed in tissues and cell types outside of the kidney (e.g. primary sensory neurons (Harrison et al, 2016), endo/epithelial cells (Cochran et al, 2015;Li et al, 2000) and migratory glial cells (Bao et al, 2012;Vandal et al, 2022), inherent expression of CD2AP in cholinergic neurons of CNS (in vivo) has not previously been identified or quantified, supporting the plausibility of a pathogenic mechanism of AD inherent to cholinergic neurons of the CNS.…”

“…CD2AP is also required for the maintenance of structure and permeability of systemic blood vessels (e.g. epithelial and endothelial cells) (Hamano et al, 2002;Li et al, 2000;Vandal et al, 2022). Interestingly, analysis of microvessels isolated from human patients with confirmed AD observed Cd2ap expression to be linearly associated with cognitive decline and Cd2ap KO from brain microvasculature (microvessels) in mice resulted in cognitive impairment (Vandal et al, 2022).…”

“…epithelial and endothelial cells) (Hamano et al, 2002;Li et al, 2000;Vandal et al, 2022). Interestingly, analysis of microvessels isolated from human patients with confirmed AD observed Cd2ap expression to be linearly associated with cognitive decline and Cd2ap KO from brain microvasculature (microvessels) in mice resulted in cognitive impairment (Vandal et al, 2022). Interaction between the vasculature and the immune system has also been implicated in the onset, progression and severity of AD (Bettcher et al, 2021;Heppner et al, 2015).…”