HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration.
Nat Neurosci
; 6(10): 1064-71, 2003 Oct.
Article
em En
| MEDLINE
| ID: mdl-14502291
ABSTRACT
The mechanisms of neurodegeneration that result in human immunodeficiency virus (HIV) type 1 dementia have not yet been identified. Here, we report that HIV-infected macrophages secrete the zymogen matrix metalloproteinase-2 (MMP-2), which is activated by exposure to MT1-MMP on neurons. Stromal cell-derived factor 1 alpha (SDF-1), a chemokine overexpressed by astrocytes during HIV infection, was converted to a highly neurotoxic protein after precise proteolytic processing by active MMP-2, which removed the N-terminal tetrapeptide. Implantation of cleaved SDF-1(5-67) into the basal ganglia of mice resulted in neuronal death and inflammation with ensuing neurobehavioral deficits that were abrogated by neutralizing antibodies to SDF-1 and an MMP inhibitor drug. Hence, this study identifies a new in vivo neurotoxic pathway in which cleavage of a chemokine by an induced metalloproteinase results in neuronal apoptosis that leads to neurodegeneration.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Complexo AIDS Demência
/
Quimiocinas CXC
/
Metaloproteinase 2 da Matriz
/
Degeneração Neural
/
Neurotoxinas
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article