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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

https://doi.org/10.2353/ajpath.2009.081113Get rights and content

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.

Supplemental material for this article can be found on http://ajp.amjpathol.org.

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