Regular ArticlesRole 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.