HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors
2001; Wiley; Volume: 49; Issue: 2 Linguagem: Inglês
10.1002/1531-8249(20010201)49
ISSN1531-8249
AutoresJames B. Johnston, Kunyan Zhang, Cláudia Silva, David R. Shalinsky, Katherine Conant, Weimin Ni, Dale Corbett, V. Wee Yong, Christopher Power,
Tópico(s)Alzheimer's disease research and treatments
ResumoThe release of potentially neurotoxic molecules by HIV-infected brain macrophages is accompanied by neuronal injury and death that results in the development of HIV-associated dementia (HAD). Among the potential neurotoxins implicated in the development of HAD is the HIV-1 transactivating protein, Tat. To investigate the mechanism by which Tat causes neurotoxicity, brain-derived Tat sequences from nondemented (Tat-ND) and demented (Tat-HAD) AIDS patients, which differed primarily in the augmenting region of Tat, were expressed in U937 monoblastoid cells and primary human macrophages. Cells expressing Tat-HAD protein exhibited elevated matrix metalloproteinase (MMP)-2 and -7 release and activation, but cells expressing Tat-ND did not exhibit enhanced MMP expression. Conditioned media from Tat-HAD–transfected cells caused significantly greater neuronal death (15.4 ± 4.3%) than did Tat-ND (4.4 ± 2.1%) or nontransfected (2.1 ± 0.8%) cell-derived conditioned media. The neurotoxicity induced by Tat-HAD was inhibited by anti–MMP-2 or -7 antibodies (p < 0.005) but not by antibodies against MMP-9 or Tat. Similarly, scid/nod mice receiving striatal implants of Tat-HAD–transfected cells exhibited greater neurobehavioral abnormalities and neuronal loss (p < 0.005) than did animals receiving Tat-ND or nontransfected cells, which were reduced by treatment with the MMP inhibitor prinomastat (p < 0.005). These findings indicate that Tat causes neuronal death through an indirect mechanism that is Tat sequence dependent and involves the induction of MMPs. Ann Neurol 2001;49:230–241
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