Rescue of adult hippocampal neurogenesis in a mouse model of HIV neurologic disease

Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Meyer 6-113, Baltimore, MD 21287, USA.
Neurobiology of Disease (Impact Factor: 5.08). 03/2011; 41(3):678-87. DOI: 10.1016/j.nbd.2010.12.002
Source: PubMed


The prevalence of central nervous system (CNS) neurologic dysfunction associated with human immunodeficiency virus (HIV) infection continues to increase, despite the use of antiretroviral therapy. Previous work has focused on the deleterious effects of HIV on mature neurons and on development of neuroprotective strategies, which have consistently failed to show a meaningful clinical benefit. It is now well established that new neurons are continuously generated in discrete regions in the adult mammalian brain, and accumulating evidence supports important roles for these neurons in specific cognitive functions. In a transgenic mouse model of HIV neurologic disease with glial expression of the HIV envelope protein gp120, we demonstrate a significant reduction in proliferation of hippocampal neural progenitors in the dentate gyrus of adult animals, resulting in a dramatic decrease in the number of newborn neurons in the adult brain. We identify amplifying neural progenitor cells (ANPs) as the first class of progenitors affected by gp120, and we also demonstrate that newly generated neurons exhibit aberrant dendritic development. Furthermore, voluntary exercise and treatment with a selective serotonin reuptake inhibitor increase the ANP population and rescue the observed deficits in gp120 transgenic mice. Thus, during HIV infection, the envelope protein gp120 may potently inhibit adult hippocampal neurogenesis, and neurorestorative approaches may be effective in ameliorating these effects. Our study has significant implications for the development of novel therapeutic approaches for HIV-infected individuals with neurologic dysfunction and may be applicable to other neurodegenerative diseases in which hippocampal neurogenesis is impaired.

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Available from: Norman J Haughey, Aug 25, 2014
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    • "For these experiments, adult rat hippocampal neuronal precursor cells (NPCs) were selected because these cells display features similar to those observed in patients with HAND (Lee et al., 2011; Okamoto et al., 2007). The cells were grown at 37°C in humidified air with 5% CO 2 in Dulbecco's modified Eagle's medium (DMEM, Life Technologies, Carlsbad, CA) containing 5% fetal bovine serum and 1% penicillin/streptomycin. "
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    ABSTRACT: Background and purpose: Anti-retrovirals have improved and extended the life expectancy of patients with HIV. However, as this population ages, the prevalence of cognitive changes is increasing. Aberrant activation of kinases, such as receptor tyrosine kinases (RTKs) and cyclin-dependent kinase 5 (CDK5), play a role in the mechanisms of HIV neurotoxicity. Inhibitors of CDK5, such as roscovitine, have neuroprotective effects; however, CNS penetration is low. Interestingly, tyrosine kinase inhibitors (TKIs) display some CDK inhibitory activity and ability to cross the blood-brain barrier. Experimental approach: We screened a small group of known TKIs for a candidate with additional CDK5 inhibitory activity and tested the efficacy of the candidate in in vitro and in vivo models of HIV-gp120 neurotoxicity. Key results: Among 12 different compounds, sunitinib inhibited CDK5 with an IC50 of 4.2 μM. In silico analysis revealed that, similarly to roscovitine, sunitinib fitted 6 of 10 features of the CDK5 pharmacophore. In a cell-based model, sunitinib reduced CDK5 phosphorylation (pCDK5), calpain-dependent p35/p25 conversion and protected neuronal cells from the toxic effects of gp120. In glial fibrillary acidic protein-gp120 transgenic (tg) mice, sunitinib reduced levels of pCDK5, p35/p25 and phosphorylated tau protein, along with amelioration of the neurodegenerative pathology. Conclusions and implications: Compounds such as sunitinib with dual kinase inhibitory activity could ameliorate the cognitive impairment associated with chronic HIV infection of the CNS. Moreover, repositioning existing low MW compounds holds promise for the treatment of patients with neurodegenerative disorders.
    Full-text · Article · Aug 2014 · British Journal of Pharmacology
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    • "Our findings support a model where the proliferation of both NPCs and GRPs is significantly reduced by HIV, with morphine interactions that can further compromise progenitor production, depending on viral strain. Tat protein clearly reduces proliferation by itself; effects of HIV supernatant reflect combined actions of multiple viral proteins such as gp120 (Lee et al. 2011) and secreted factors. Reduced proliferation predicts overall reduction in progenitor populations, which was observed. "
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    ABSTRACT: HIV-associated neurocognitive disorders (HANDs) are common sequelae of human immunodeficiency virus (HIV) infection, even when viral titers are well controlled by antiretroviral therapy. Evidence in patients and animal models suggests that neurologic deficits are increased during chronic opiate exposure. We have hypothesized that central nervous system (CNS) progenitor cells in both adult and developing CNS are affected by HIV infection and that opiates exacerbate these effects. To examine this question, neural progenitors were exposed to HIV-1 Tat(1-86) in the developing brain of inducible transgenic mice and in vitro. We examined whether Tat affected the proliferation or balance of progenitor populations expressing nestin, Sox2, and Olig2. Disease relevance was further tested by exposing human-derived progenitors to supernatant from HIV-1 infected monocytes. Studies concentrated on striatum, a region preferentially targeted by HIV and opiates. Results were similar among experimental paradigms. Tat or HIV exposure reduced the proliferation of undifferentiated (Sox2(+) ) progenitors and oligodendroglial (Olig2(+) ) progenitors. Coexposure to morphine exacerbated the effects of Tat or HIV-1(SF162) supernatant, but partially reversed HIV-1(IIIB) supernatant effects. Populations of Sox2(+) and Olig2(+) cells were also reduced by Tat exposure, although progenitor survival was unaffected. In rare instances, p24 immunolabeling was detected in viable human progenitors by confocal imaging. The vulnerability of progenitors is likely to distort the dynamic balance among neuron/glial populations as the brain matures, perhaps contributing to reports that neurologic disease is especially prevalent in pediatric HIV patients. Pediatric disease is atypical in developed regions but remains a serious concern in resource-limited areas where infection occurs commonly at birth and through breast feeding. © 2012 Wiley Periodicals, Inc.
    Full-text · Article · Dec 2012 · Glia
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    • "Hippocampal dysfunction in HAND may include atrophy, neuronal cell loss, and functional magnetic resonance imaging abnormalities (Archibald et al. 2004; Castelo et al. 2006; Maki and Martin-Thormeyer 2009; Sa et al. 2004; Wiley et al. 1998). Studies in rodent models also suggest that HIV infection has multiple deleterious effects on the hippocampus, including synaptic loss and cell death (Kim et al. 2008), impaired neurogenesis (Lee et al. 2011), and disruption of NMDA receptor trafficking (Xu et al. 2011). Despite considerable evidence that HAND affects the hippocampus, only a handful of studies in HIVinfected patients have incorporated tests of spatial memory into their batteries of neurocognitive assessments (Maki and Martin-Thormeyer 2009; Schouten et al. 2011). "
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    ABSTRACT: HIV-associated neurocognitive disorders (HAND) continue to be a neurological complication of HIV infection in the era of combined antiretroviral therapy. Hippocampal neurodegeneration and dysfunction occurs as a result of HIV infection, but few studies to date have assesses spatial learning and memory function in patients with HAND. We used the Memory Island (MI) test to study the effects of HIV infection, apolipoprotein E (ApoE) allele status, and cerebral spinal fluid (CSF) ApoE protein levels on spatial learning and memory in our cohort of Hispanic women. The MI test is a virtual reality-based computer program that tests spatial learning and memory and was designed to resemble the Morris Water Maze test of hippocampal function widely used in rodent studies. In the current study, HIV-seropositive women (n = 20) and controls (n = 16) were evaluated with neuropsychological (NP) tests, the MI test, ApoE, and CSF ApoE assays. On the MI, the HIV-seropositive group showed significant reduced learning and delayed memory performance compared with HIV-seronegative controls. When stratified by cognitive performance on NP tests, the HIV-seropositive, cognitively impaired group performed worse than HIV-seronegative controls in ability to learn and in the delayed memory trial. Interestingly, differences were observed in the results obtained by the NP tests and the MI test for ε4 carriers and noncarriers: NP tests showed effects of the ε4 allele in HIV-seronegative women but not HIV-seropositive ones, whereas the converse was true for the MI test. Our findings suggest that the MI test is sensitive in detecting spatial deficits in HIV-seropositive women and that these deficits may arise relatively early in the course of HAND.
    Full-text · Article · Sep 2012 · Journal of NeuroVirology
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