title: Tissue inhibitor of metalloproteinases-1 protects human neurons from staurosporine and HIV-1-induced apoptosis: mechanisms and relevance to HIV-1-associated dementia.
abstract: HIV-1-associated dementia (HAD)-relevant proinflammatory cytokines robustly induce astrocyte tissue inhibitor of metalloproteinases-1 (TIMP-1). As TIMP-1 displays pleotropic functions, we hypothesized that TIMP-1 expression may serve as a neuroprotective response of astrocytes. Previously, we reported that chronically activated astrocytes fail to maintain elevated TIMP-1 expression, and TIMP-1 levels are lower in the brain of HAD patients; a phenomenon that may contribute to central nervous system pathogenesis. Further, the role of TIMP-1 as a neurotrophic factor is incompletely understood. In this study, we report that staurosporine (STS) and HIV-1(ADA) virus, both led to induction of apoptosis in cultured primary human neurons. Interestingly, cotreatment with TIMP-1 protects neurons from apoptosis and reverses neuronal morphological changes induced by these toxins. Further, the anti-apoptotic effect was not observed with TIMP-2 or -3, but was retained in a mutant of the N-terminal TIMP-1 protein with threonine-2 mutated to glycine (T2G) that is deficient in matrix metalloproteinase (MMP)-1, -2 and -3 inhibitory activity. Therefore, the mechanism is specific to TIMP-1 and partially independent of MMP-inhibition. Additionally, TIMP-1 modulates the Bcl-2 family of proteins and inhibits opening of mitochondrial permeability transition pores induced by HIV-1 or STS. Together, these findings describe a novel function, mechanism and direct role of TIMP-1 in neuroprotection, suggesting its therapeutic potential in HAD and possibly in other neurodegenerative diseases.
authors: Department of Cell Biology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors: Ashutosh
authors: C
authors: C
authors: Chao
authors: K
authors: K
authors: Borgmann
authors: K
authors: K
authors: Brew
authors: A
authors: A
authors: Ghorpade
mesh_terms: D015526:AIDS Dementia Complex / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D017209:Apoptosis; D002478:Cells, Cultured; D053938:DNA Fragmentation; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D019311:Staurosporine / Q000633:toxicity*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019311:Staurosporine