Amyloid beta (A beta) levels are increased in HIV-1 infected brains due to not yet fully understood mechanisms. In the present study, we investigate the role of lipid rafts, functional caveolae, and caveolae-associated signaling in HIV-1-induced A beta accumulation in HBMEC. Both silencing of caveolin-1 (cav-1) and disruption of lipid rafts by pretreatment with beta-methyl-cyclodextrin (MCD) protected against A beta accumulation in HBMEC. Exposure to HIV-1 and A beta activated caveolae-associated Ras and p38. While inhibition of Ras by farnesylthiosalicylic acid (FTS) effectively protected against HIV-1-induced accumulation of A beta, blocking of p38 did not have such an effect. We also evaluated the role of caveolae in HIV-1-induced upregulation of the receptor for advanced glycation end products (RAGE), which regulates A beta transfer from the blood stream into the central nervous system. HIV-1-induced RAGE expression was prevented by infecting HBMEC with cav-1 specific shRNA lentiviral particles or by pretreatment of cells with FTS. Overall, the present results indicate that A beta accumulation in HBMEC is lipid raft and caveolae dependent and involves the caveolae-associated Ras signaling. (C) 2012 Elsevier Inc. All rights reserved.