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

Abstract

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 (Aβ) 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 Aβ 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 Aβ generation, we tested the hypothesis that caffeine blocks HIV-1 Tat-induced Aβ generation and tau phosphorylation. In SH-SY5Y cells over-expressing wild-type amyloid beta precursor protein (AβPP), we demonstrated that HIV-1 Tat significantly increased secreted levels and intracellular levels of Aβ as well as cellular protein levels of phosphorylated tau. Caffeine significantly decreased levels of secreted and cellular levels of Aβ, and significantly blocked HIV-1 Tat-induced increases in secreted and cellular levels of Aβ. 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.

Effect of Caffeine and Other Methylxanthines on Aβ-Homeostasis in SH-SY5Y Cells

“…As shown in Figure 2 all investigated MTXs reduced the total secreted Aβ level in a similar range. In line with current literature describing impaired Aβ generation in presence of caffeine [57,58], caffeine significantly reduced secreted Aβ level to 84.5% ± 5.4% ( p = 0.0205) in our cellular system (Figure 2). A comparable protective effect regarding total Aβ level was obtained for theophylline, theobromine and propentofylline.…”

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

“…Tat-mediated toxicity is potentiated by the production of Aβ [197, 198]. Caffeine has been shown to be a therapeutic intervention that overcomes Tat-mediated endosomal dysfunction [199]. …”

Anti-diarrheal Activity of Caffeine: A Modulatory Effect with Loperamide and through 6FH5 (PIK3CG) Protein Interaction Pathway

“…39 CAF is evident to block HIV-1 Tat protein in SH-SY5Y cells. 40 CNS also controls gastrointestinal motility and secretion, therefore modulates gastrointestinal functions. 41 CAF is widely known CNS stimulant methylxanthine alkaloid class drug, therefore, it can act through this system.…”