Endolysosome involvement in HIV-1 transactivator protein-induced neuronal amyloid beta production

Xuesong Chen, Liang Hui, Nicholas H. Geiger, Norman J. Haughey, Jonathan D. Geiger

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2370-2378
Number of pages9
JournalNeurobiology of Aging
Volume34
Issue number10
DOIs
StatePublished - Oct 1 2013

Fingerprint

Human Immunodeficiency Virus rev Gene Products
Amyloid
HIV-1
Alzheimer Disease
Coloring Agents
Neurons
Serum Amyloid A Protein
Amyloid beta-Peptides

Keywords

  • Amyloid beta
  • BACE-1
  • Endolysosome
  • HIV-1 Tat
  • pH

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Endolysosome involvement in HIV-1 transactivator protein-induced neuronal amyloid beta production. / Chen, Xuesong; Hui, Liang; Geiger, Nicholas H.; Haughey, Norman J.; Geiger, Jonathan D.

In: Neurobiology of Aging, Vol. 34, No. 10, 01.10.2013, p. 2370-2378.

Research output: Contribution to journalArticle

Chen, Xuesong ; Hui, Liang ; Geiger, Nicholas H. ; Haughey, Norman J. ; Geiger, Jonathan D. / Endolysosome involvement in HIV-1 transactivator protein-induced neuronal amyloid beta production. In: Neurobiology of Aging. 2013 ; Vol. 34, No. 10. pp. 2370-2378.
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