Reconstitution of human immunodeficiency virus-induced neurodegeneration using isolated populations of human neurons, astrocytes, and microglia and neuroprotection mediated by insulin-like growth factors |
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Authors: | Jianbin Wang Dana Gabuzda |
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Institution: | Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. |
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Abstract: | Primary human neuron cultures are an important in vitro model system for studies on mechanisms involved in human immunodeficiency virus (HIV)-associated dementia (HAD) and other
neurological disorders. Here, more than 80 cell surface antigens were screened to identify a marker that could readily distinguish
between neurons and astrocytes and found that neurons lack CD44 surface expression, whereas astrocytes and other cell types
in brain are CD44+. Neurons and astrocytes were isolated from human fetal brain based on differential expression of CD44. Using purified neurons
cocultured with astrocytes and/or microglia, it was demonstrated that HIV infection of microglia induces cellular activation
and production of soluble factors that activate uninfected microglia and astrocytes and induce neuronal cell death. Activated
astrocytes promoted HIV replication in microglia, thereby amplifying HIV-induced neurotoxicity. A screen for 120 cytokine/proteins
detected upregulation of insulin-like growth factor (IGF)-binding protein (IGFBP)-2, interleukin (IL)-6, and CCL8/MCP-2 (monocyte
chemoattractant protein 2) in supernatants of HIV-infected brain cell cultures. IGF-1 and -2 increased neuronal survival in
HIV-infected brain cell cultures, whereas IGFBP-2 inhibited prosurvival effects of these growth factors. These findings identify
CD44 as a marker that can be used to sort neurons from other cell types in brain, suggest the importance of microglia-astrocyte
interactions in neurodegenerative mechanisms associated with HIV infection, and indicate a role for insulin-like growth factors
in neuroprotection from HIV-induced neurodegeneration. The ability to reconstitute brain cultures using isolated populations
of neurons, astrocytes, and microglia will be valuable for studies on pathogenic mechanisms in HAD and other neurological
disorders, and will also facilitate neuroactive drug discovery. |
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