title: Endolysosome involvement in HIV-1 transactivator protein-induced neuronal amyloid beta production.
abstract: The increased life expectancy of people living with HIV-1/AIDS is accompanied by increased prevalence of HIV-1-associated neurocognitive disorder. As well, these individuals are increasingly experiencing Alzheimer's disease (AD)-like neurocognitive problems and neuropathological features such as increased deposition of amyloid beta (Aβ) protein. Findings that Aβ production occurs largely in endolysosomes, that HIV-1 transactivator protein (Tat) disrupts endolysosome function-an early pathological feature of AD-and that HIV-1 Tat can increase Aβ levels prompted us to test the hypothesis that endolysosome dysfunction is associated with HIV-1 Tat-induced increases in neuronal Aβ generation. Using primary cultured rat hippocampal neurons, we found that treatment with HIV-1 Tat caused such morphological changes as enlargement of endolysosomes identified with LysoTracker dye and such functional changes as elevated endolysosome pH measured ratiometrically with LysoSensor dye. The HIV-1 Tat-induced changes in endolysosome function preceded temporally HIV-1 Tat-induced increases in Aβ generation measured using enzyme-linked immunosorbent assay. In addition, we demonstrated that HIV-1 Tat increased endolysosome accumulation of Aβ precursor protein and Aβ identified using immunostaining with 4G8 antibodies. Furthermore, we demonstrated that treatment of neurons with HIV-1 Tat increased endolysosome accumulation of beta amyloid-converting enzyme, the rate-limiting enzymatic step for Aβ production, and enhanced beta amyloid-converting enzyme activity. Together, our findings suggest that HIV-1 Tat increases neuronal Aβ generation and thereby contributes to the development of AD-like pathology in HIV-1-infected individuals by disturbing endolysosome structure and function.
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA. xuesong.chen@med.und.edu
authors.forename: Xuesong
authors.initials: X
authors.lastname: Chen
authors.forename: Liang
authors.initials: L
authors.lastname: Hui
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Geiger
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Haughey
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Geiger
mesh_terms: D015526:AIDS Dementia Complex / Q000209:etiology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D015497:HIV-1; D006624:Hippocampus / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D054321:rev Gene Products, Human Immunodeficiency Virus / Q000009:adverse effects*
chemical_list: D016229:Amyloid beta-Peptides; D054321:rev Gene Products, Human Immunodeficiency Virus; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat
keywords: Amyloid beta; BACE-1; Endolysosome; HIV-1 Tat; pH