Date Published: June 13, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Chunjiang Yu, Srinivas D. Narasipura, Maureen H. Richards, Xiu‐Ti Hu, Bryan Yamamoto, Lena Al‐Harthi.
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.
With the introduction of combined antiretroviral therapy (cART), HIV has been transformed from a deadly virus to a chronic infection linked to a number of comorbid conditions associated with an aging population. In particular, HIV‐infected individuals are at an increased risk of neurocognitive and motor impairments (Saylor et al., 2016) termed HIV‐associated neurocognitive disorders (HAND). Incidences of HAND are expected to increase as the HIV+ population is living longer and aging. HAND is driven by complex interactions of HIV invasion into the central nervous system (CNS), inflammatory responses in the CNS that ensue, and comorbid factors such as illicit drug abuse. Methamphetamine (meth), in particular, is a potent psychostimulant (Hser et al., 2008) and is frequently abused in the HIV/AIDS population. HAND is more severe among HIV+ individuals who are meth abusers than those who are not (Nath et al., 2002; Chana et al., 2006; Purohit et al., 2011). Further, meth users who are HIV negative also experience neurocognitive deficits that persist even following periods of abstinence from meth use (Scott et al., 2007; Iudicello et al., 2010). The underlying mechanisms by which HIV and meth dysregulate resident brain cells are not entirely clear. We evaluated here the impact of HIV and meth on cellular aging in astrocytes.
Cell senescence and its associated SASP may drive premature organism aging (Kennedy et al., 2014). Astrocyte senescence is implicated in human brain aging (Kang et al., 2015) and in neurodegenerative diseases such as Alzheimer’s (Bhat et al., 2012) and Parkinson’s disease (Chinta et al., 2013). HAND exhibits many features of neuroinflammation, which is a common thread among a number of other premature aging and neurodegenerative diseases, yet whether HIV neuroinvasion impacts astrocyte senescence is not clear. We evaluated here the impact of HIV and meth on astrocyte senescence. We show that both HIV and meth induce astrocyte senescence as evaluated by enhanced expression of senescence biomarkers such as SA‐βGAL, p16INK4A, predominance of cells in S phase of the cell cycle, and a flat morphology of astrocytes. The HIV and meth effect on astrocyte senescence is additive in nature. Most significantly, when astrocytes were induced into senescence by meth, the conditioned medium increased neuronal apoptosis, which is consistent with neuron damage in chronic meth abusers. Presumably, the conditioned media of senescent astrocytes may either reflect a senescence‐associated secretion phenotype (SASP), which is characterized by elevated levels of potent inflammatory cytokines (Campisi, 2013), or lack key neurotrophic factors relevant to maintaining neuronal health. SASP could also propagate senescence in a paracrine manner. In oncogene‐induced senescence models, both in vitro and in vivo, increased levels of IL‐1α induced SASP and senescence in neighboring cells (Acosta et al., 2013). Thus, it is conceivable that meth‐ and HIV‐induced senescence in astrocytes would amplify senescence in neighboring astrocytes and even neuronal stem cells in the surrounding regions.
This work was supported by R01 DA 033966 (LA), R01 NS060632 (LA), R01 NS084817 (XH), and DA007606 (BY). National Institutes of Health (Grant / Award Number: DA007606,R01 DA 033966,R01 NS060632 and R01 NS084817).