title: 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.
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 504 Hamline St., Grand Forks, ND, 58203, USA.
authors.forename: Mahmoud L
authors.initials: ML
authors.lastname: Soliman
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 504 Hamline St., Grand Forks, ND, 58203, USA. jonathan.geiger@med.und.edu.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Geiger
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 504 Hamline St., Grand Forks, ND, 58203, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Chen
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D054322:tat Gene Products, Human Immunodeficiency Virus; D016875:tau Proteins; D002110:Caffeine
keywords: Amyloid beta; BACE-1; Caffeine; Endolysosomes; HIV-1 Tat; Tau phosphorylation