HIV and drug abuse mediate astrocyte senescence in a β-catenin-dependent manner leading to neuronal toxicity

Chunjiang Yu, Srinivas D. Narasipura, Maureen H. Richards, Xiu Ti Hu, Bryan Yamamoto, Lena Al-Harthi

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Emerging evidence suggests that cell senescence plays an important role in aging-associated diseases including neurodegenerative diseases. HIV leads to a spectrum of neurologic diseases collectively termed HIV-associated neurocognitive disorders (HAND). Drug abuse, particularly methamphetamine (meth), is a frequently abused psychostimulant among HIV+ individuals and its abuse exacerbates HAND. The mechanism by which HIV and meth lead to brain cell dysregulation is not entirely clear. In this study, we evaluated the impact of HIV and meth on astrocyte senescence using in vitro and several animal models. Astrocytes constitute up to 50% of brain cells and play a pivotal role in marinating brain homeostasis. We show here that HIV and meth induce significant senescence of primary human fetal astrocytes, as evaluated by induction of senescence markers (β-galactosidase and p16INK 4A), senescence-associated morphologic changes, and cell cycle arrest. HIV- and meth-mediated astrocyte senescence was also demonstrated in three small animal models (humanized mouse model of HIV/NSG-huPBMCs, HIV-transgenic rats, and in a meth administration rat model). Senescent astrocytes in turn mediated neuronal toxicity. Further, we show that β-catenin, a pro-survival/proliferation transcriptional co-activator, is downregulated by HIV and meth in human astrocytes and this downregulation promotes astrocyte senescence while induction of β-catenin blocks HIV- and meth-mediated astrocyte senescence. These studies, for the first time, demonstrate that HIV and meth induce astrocyte senescence and implicate the β-catenin pathway as potential therapeutic target to overcome astrocyte senescence.

Original languageEnglish (US)
JournalAging Cell
DOIs
StateAccepted/In press - 2017

Fingerprint

Catenins
Astrocytes
Substance-Related Disorders
Methamphetamine
HIV
Brain
Down-Regulation
Animal Models
Galactosidases
Transgenic Rats
Cell Aging
Cell Cycle Checkpoints
Nervous System Diseases
Neurodegenerative Diseases

Keywords

  • Astrocyte
  • HIV
  • Methamphetamine
  • Senescence
  • β-catenin

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

HIV and drug abuse mediate astrocyte senescence in a β-catenin-dependent manner leading to neuronal toxicity. / Yu, Chunjiang; Narasipura, Srinivas D.; Richards, Maureen H.; Hu, Xiu Ti; Yamamoto, Bryan; Al-Harthi, Lena.

In: Aging Cell, 2017.

Research output: Contribution to journalArticle

Yu, Chunjiang ; Narasipura, Srinivas D. ; Richards, Maureen H. ; Hu, Xiu Ti ; Yamamoto, Bryan ; Al-Harthi, Lena. / HIV and drug abuse mediate astrocyte senescence in a β-catenin-dependent manner leading to neuronal toxicity. In: Aging Cell. 2017.
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