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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.

journal_name

Neurobiol Aging

journal_title

Neurobiology of aging

authors

Chen X,Hui L,Geiger NH,Haughey NJ,Geiger JD

doi

10.1016/j.neurobiolaging.2013.04.015

subject

Has Abstract

pub_date

2013-10-01 00:00:00

pages

2370-8

issue

10

eissn

0197-4580

issn

1558-1497

pii

S0197-4580(13)00180-2

journal_volume

34

pub_type

杂志文章

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