Neural progenitor cells (NPC) persist throughout life serving to replenish neurons and glia (astrocytes and' oligodendrocytes). This is facilitated through NPC migration, proliferation and differentiation. This process of neurogenesis is negatively -affected during neurodegenerative disorders [including HIV-1 associated dementia (HAD), Alzheimer's and Parkinson's diseases]. The end result is that dead or injured neurons and glia are not replaced at rates that can affect disease progression. We posit that the central pathogenic feature of HAD, the induction of a metabolic encephalopathy fueled by HIV-1 infected and activated brain mononuclear phagocytes (MP;perivascular and brain macrophages and microglia), inhibits neurogenesis but enhances gliogenesis. This effect may be linked to MP secreted TNF-a and MP mediated modification/degradation of stromal cell-derived factor 1 (SDF-1), a ligand for a chemokine receptor CXCR4. Aberrations between SDF-1 and CXCR4 can affect neural repair by altering NPC mobility. At least two lines of evidence support this notion. First, CXCR4 is highly expressed on human NPC and mediate NPC migration. Second, SDF-1 is released in response to glial activation and is elevated in the cerebrospinal fluid of HAD patients. Importantly, SDF-1 (cleaved by activated matrix metalloproteinase-2) and TNF-a/other proinflammatory cytokines are produced by HIV-1 infected and activated MP. Thus, this proposal seeks to examine the role for HIV-1 infected and activated MP on neuro- and gliogenesis and its links to brain inflammation. We propose activated astrocytes produce SDF-1 and promote neurogenesis. This function is attenuated by HIV-1-infected and immune-activated macrophages through proteolytic modification/degradation of secreted SDF-1, resulting in impairment of SDF-1/CXCR4 mediated NPC migration. Furthermore, MP-secreted inflammatory cytokines, such as TNF-a, inhibits neurogenesis and promotes gliogenesis, generating an environment detrimental to CNS repair. Using a human NPC culture system combined with HIV-1 encephalitis mice, this project will utilize laboratory assays that mimic IV-1 infection and immune activation of brain MP. This is done to investigate the effect of CNS immune response on neurogenesis as it would occur during HAD. Elucidation of the mechanisms by which SDF- 1/CXCR4 and cytokines influence neurogenesis may identify new therapeutic strategies for HAD and other neurodegenerative disorders.
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