Role of the Macrophage Inflammatory Protein-1α/CC Chemokine Receptor 5 Signaling Pathway in the Neuroinflammatory Response and Cognitive Deficits Induced by β-Amyloid Peptide
The hallmarks of Alzheimer’s disease include the deposition of β-amyloid (Aβ), neuroinflammation, and cognitive deficits. The accumulation of activated glial cells in cognitive-related areas is critical for these alterations, although little is known about the mechanisms driving this event. Herein we used macrophage inflammatory protein-1α (MIP-1α−/−)- or CC-chemokine receptor 5 (CCR5−/−)-deficient mice to address the role played by chemokines in molecular and behavioral alterations induced by Aβ1–40. Aβ1–40 induced a time-dependent increase of MIP-1α mRNA followed by accumulation of activated glial cells in the hippocampus of wild-type mice. MIP-1α−/− and CCR5−/− mice displayed reduced astrocytosis and microgliosis in the hippocampus after Aβ1–40 administration that was associated with decreased expression of cyclooxygenase-2 and inducible nitric oxide synthase, as well as reduced activation of nuclear factor-κB, activator protein-1 and cyclic AMP response element-binding protein. Furthermore, MIP-1α−/− and CCR5−/− macrophages showed impaired chemotaxis in vitro, although cytokine production in response to Aβ1–40 was unaffected. Notably, the cognitive deficits and synaptic dysfunction induced by Aβ1–40 were also attenuated in MIP-1α−/− and CCR5−/− mice. Collectively, these results indicate that the MIP-1α/CCR5 signaling pathway is critical for the accumulation of activated glial cells in the hippocampus and, therefore, for the inflammation and cognitive failure induced by Aβ1–40. Our data suggest MIP-1α and CCR5 as potential therapeutic targets for Alzheimer’s disease treatment.
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Supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, the Programa de Apoio aos Núcleos de Excelência, and the Fundação de Apoio a Pesquisa do Estado de Santa Catarina, all from Brazil. G.F.P. and P.P. are Ph.D. students in pharmacology receiving grants from CNPq. F.S.D. and R.M. hold postdoctoral fellowships from CNPq.