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Impaired neurogenesis and neurite outgrowth in an HIV-gp120 transgenic model is reversed by exercise via BDNF production and Cdk5 regulation

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An Editorial to this article was published on 27 September 2013

Abstract

Human immunodeficiency virus (HIV) infection-associated neurocognitive disorders is accompanied with brain atrophy. In these patients, impairment of adult neurogenesis and neurite outgrowth in the hippocampus may contribute to cognitive dysfunction. Although running exercises can enhance neurogenesis and normalize neurite outgrowth, the underlying molecular mechanisms are not well understood. The HIV envelope protein, gp120, has been shown to impair neurogenesis. Using a gp120 transgenic mouse model, we demonstrate that exercise stimulated neural progenitor cell (NPC) proliferation in the hippocampal dentate gyrus and increased the survival rate and generation of newborn cells. However, sustained exercise activity was necessary as the effects were reversed by detraining. Exercise also normalized dendritic outgrowth of neurons. Furthermore, it increased the expression of hippocampal brain-derived neurotrophic factor (BDNF) and normalized hyperactivation of cyclin-dependent kinase 5 (Cdk5). Hyperactivated Cdk5 or gp120 treatment led to aberrant neurite outgrowth and BDNF treatment normalized the neurite outgrowth in NPC cultures. These results suggest that sustained exercise has trophic activity on the neuronal lineage which is mediated by Cdk5 modulation of the BDNF pathway.

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Acknowledgments

We thank Dr. Valerie Toodle for technical assistance. This work was supported by grants from the NIH (R01-DA024593; R01-NS039253) and NINDS intramural funds.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Section of Infections of the Nervous System, National Institutes of Health, M.D. Bldg 10, Room 7C-103, 10 Center Drive, Bethesda, MD, 20892, USA

    Myoung-Hwa Lee, Tongguang Wang, Richa Tyagi & Avindra Nath

  2. Neuronal Cytoskeletal Protein Regulatory Section, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA

    Niranjana D. Amin & Harish C. Pant

  3. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Arun Venkatesan

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  1. Myoung-Hwa Lee
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  2. Niranjana D. Amin
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  3. Arun Venkatesan
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  4. Tongguang Wang
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Correspondence to Avindra Nath.

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Fig. S1

proBDNF expression was increased in the gp120 transgenic mice. a Shown are sample immunoreactive bands from Western blot analysis. Lysates from the hippocampus of the wild-type and gp120 transgenic mice were subjected to Western blot analysis for proBrain-derived neurotrophic factor (proBDNF; 34 kDa) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH; as an internal control, 35 kDa). b The ratio of proBDNF/GAPDH was quantified. proBDNF expression was upregulated in the hippocampus of the gp120 transgenic mice. Values represent mean ± SEM (n = 3 animals in each group; *p < 0.05, one-way ANOVA followed by Duncan's test). (PDF 23 kb)

Fig. S2

Rolipram did not reinforce NPC proliferation and survival effect of exercise on newly generated cell. a Experimental design. To study the effect of the PDE4 inhibitor, rolipram on NPC proliferation, mice received rolipram (3 mg/kg) daily for ten consecutive days at 11 days after treatment (running or sedentary activity) for 10 days. Mice were administered a single dose of BrdU and killed 24 h later. b Rolipram treatment after 10 days of running failed to counteract the effect of detraining on NPC proliferation. Values represent mean ± SEM (n = 5 animals in each group; one-way ANOVA followed by Duncan's test). c Experimental design. For survival studies, mice were given 50 mg/kg of BrdU at 2-h intervals for 6 h. Rolipram (3 mg/kg) was administered to mice daily for ten consecutive days at 11 days after BrdU labeling. The mice were then killed either 1 or 21 days after the initial BrdU injection. d The survival rate was not increased by rolipram treatment after 10 days of running. Values represent mean ± SEM (n = 5 animals in each group; one-way ANOVA followed by Duncan's test). (PDF 91 kb)

Fig. S3

The effect of exercise on NPC proliferation was independent of NE signaling. a Experimental design. Mice were allowed free access to a running wheel for 10 days. Intraperitoneal injections of the β-adrenergic antagonist, propranolol at 5 mg/kg were given for the last 3 days of a 10-day period of exercise. All the animals were analyzed 24 h after BrdU injection. b Exercise increased proliferating NPCs both in the wild-type and gp120 transgenic mice, but propranolol failed to block exercise-induced increase in NPC proliferation. Values represent mean ± SEM (n = 5 animals in each group; one-way ANOVA followed by Duncan's test). (PDF 45 kb)

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Lee, MH., Amin, N.D., Venkatesan, A. et al. Impaired neurogenesis and neurite outgrowth in an HIV-gp120 transgenic model is reversed by exercise via BDNF production and Cdk5 regulation. J. Neurovirol. 19, 418–431 (2013). https://doi.org/10.1007/s13365-013-0194-6

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