Alzheimer disease (AD) is the most prevalent form of dementia in the elderly. Vascular degeneration plays a critical role in AD pathogenesis. For instance, APOE4 allele, the main genetic risk factor for AD, is linked to reduced cerebral blood flow and increased blood brain barrier (BBB) leakiness. CD2-associated protein (CD2AP) is an adaptor protein that regulates receptor endocytosis and recycling. Two single nucleotide polymorphisms in CD2AP are associated with higher risk for AD and levels of CD2AP are decreased in lymphocytes of sporadic AD patients. Recent human studies also show that CD2AP is linked to the burden of Aβ plaques, memory deficits and modulates AD symptoms in APOE4 patients. Interestingly, CD2AP is enriched in the brain microvascular endothelial cells (BMECs), a key component of the brain microvasculature. However, the basic functions of CD2AP in BMECs and its contribution to brain vasculature dysfunction in AD remain totally unknown.
Here we show that siRNA-mediated depletion of CD2AP in both human brain endothelial cell line and mouse primary BMECs leads to the deregulation of proteins involved in AD pathogenesis. Of particular interest, we found that CD2AP interacts with one of these proteins, ApoER2, the receptor for ApoE that is targeted to degradation upon ligation by AD allele ApoE4. Similar to ApoE4, CD2AP loss reduced the levels of ApoER2. Finally, we discovered that downregulation of ApoER2 in CD2AP-depleted cells is modulated by Rab5 GTPase activity.