Caffeine Blocks HIV-1 Tat-Induced Amyloid Beta Production and Tau Phosphorylation

The increased life expectancy of people living with HIV-1 who are taking effective anti-retroviral therapeutics is now accompanied by increased Alzheimer's disease (AD)-like neurocognitive problems and neuropathological features such as increased levels of amyloid beta (A beta) and phosphorylated tau proteins. Others and we have shown that HIV-1 Tat promotes the development of AD-like pathology. Indeed, HIV-1 Tat once endocytosed into neurons can alter morphological features and functions of endolysosomes as well as increase A beta generation. Caffeine has been shown to have protective actions against AD and based on our recent findings that caffeine can inhibit endocytosis in neurons and can prevent neuronal A beta generation, we tested the hypothesis that caffeine blocks HIV-1 Tat-induced A beta generation and tau phosphorylation. In SH-SY5Y cells over-expressing wild-type amyloid beta precursor protein (A beta PP), we demonstrated that HIV-1 Tat significantly increased secreted levels and intracellular levels of A beta as well as cellular protein levels of phosphorylated tau. Caffeine significantly decreased levels of secreted and cellular levels of A beta, and significantly blocked HIV-1 Tat-induced increases in secreted and cellular levels of A beta. Caffeine also blocked HIV-1 Tat-induced increases in cellular levels of phosphorylated tau. Furthermore, caffeine blocked HIV-1 Tat-induced endolysosome dysfunction as indicated by decreased protein levels of vacuolar-ATPase and increased protein levels of cathepsin D. These results further implicate endolysosome dysfunction in the pathogenesis of AD and HAND, and by virtue of its ability to prevent and/or block neuropathological features associated with AD and HAND caffeine might find use as an effective adjunctive therapeutic agent.