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

Summary 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 methamphetami...

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Published in:	Aging cell 2017-10, Vol.16 (5), p.956-965
Main Authors:	Yu, Chunjiang, Narasipura, Srinivas D., Richards, Maureen H., Hu, Xiu‐Ti, Yamamoto, Bryan, Al‐Harthi, Lena
Format:	Article
Language:	eng
Subjects:	AIDS Dementia Complex - complications AIDS Dementia Complex - genetics AIDS Dementia Complex - metabolism AIDS Dementia Complex - physiopathology Analysis Animals Animals, Genetically Modified astrocyte Astrocytes - metabolism Astrocytes - pathology Astrocytes - virology beta Catenin - genetics beta Catenin - metabolism Cellular Senescence - genetics Central Nervous System Stimulants - adverse effects Cyclin-Dependent Kinase Inhibitor p16 - genetics Cyclin-Dependent Kinase Inhibitor p16 - metabolism Disease Models, Animal DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Drug abuse Drug therapy Gene Expression Regulation Genetic engineering Health aspects HIV HIV (Viruses) HIV-1 - pathogenicity HIV-1 - physiology Humans Male Methamphetamine Methamphetamine - adverse effects Mice Neurons Neurons - metabolism Neurons - pathology Neurons - virology Original Primary Cell Culture Rats senescence Signal Transduction Substance-Related Disorders - complications Substance-Related Disorders - genetics Substance-Related Disorders - metabolism Substance-Related Disorders - physiopathology β‐catenin
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Summary:	Summary 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 p16INK4A), 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.
ISSN:	1474-9718 1474-9726