A new element of HIV-1 epidemiology is an increase in the older population infected with HIV-1. This phenomenon is of significant concern because the increasing age may have a detrimental effect on their cognitive functions and facilitate and enhance the development of neurodegenerative diseases in HIV-infected patients. The present application is based on our recent observations that exposure to HIV-1 results in a significant increase in amyloid beta (A2) levels in human brain microvascular endothelial cells. These findings are consistent with strong clinical evidence that indicates increased amyloid deposition in the brain of HIV-1-infected patients. Because blood-borne A2 is the main source of amyloid deposition in the brain, we formed the central hypothesis of the present proposal that HIV-1-induced specific alterations of transporter activities in brain endothelial cells results in intracellular A2 accumulation and its transendothelial passage. We identified that HIV-1-induced activity of the receptor for advanced glycation end products (RAGE) and alterations of ABC efflux transporters (namely, P-glycoprotein [Pgp] and breast cancer resistance protein [BCRP]), may be involved in these processes. It is striking to note that these transporters are associated with cell membrane lipid rafts or their specific subset called caveolae. In addition, expression of these transporters appears to be regulated by small GTPases, such as the Ras and Rho pathways, that are also localized in lipid rafts/caveolae. Therefore, we propose that functional lipid rafts and caveolae provide the signaling platform that is detrimental for HIV-1-induced vascular mechanisms leading to A2 accumulation in the CNS. Data arising from our proposal will be critical for a better understanding of the molecular mechanisms underlying HIV-1-related cerebrovascular injury in older HIV-1-infected individuals. The results generated by the proposed research are also likely to be relevant to other neurodegenerative diseases that have significant cerebrovascular components and are associated with amyloid accumulation, such as Alzheimer's disease.