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 beta-amyloid (A beta), 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-1 alpha (MIP-1 alpha(-/-))- or CC-chemokine receptor 5 (CCR5(-/-))-deficient mice to address the role played by chemokines in molecular and behavioral alterations induced by A beta(1-40). A beta(1-40) induced a time-dependent increase of MIP-1 alpha mRNA followed by accumulation of activated glial cells in the hippocampus of wild-type mice. MIP-1 alpha(-/-) and CCR5(-/-) mice displayed reduced astrocytosis and microgtiosis in the hippocampus after A beta(1-40) administration that was associated with decreased expression of cyclooxygenase-2 and inducible nitric oxide synthase, as well as reduced activation of nuclear factor-kappa B, activator protein-1 and cyclic AMP response element-binding protein. Furthermore, MIP-1 alpha(-/-) and CCR5(-/-) macrophages showed impaired chemotaxis in vitro, although cytokine production in response to A beta(1-40) was unaffected. Notably, the cognitive deficits and synaptic dysfunction induced by A beta(1-40) were also attenuated in MIP-1 alpha(-/-) and CCR5(-/-) mice. Collectively, these results indicate that the MIP-1 alpha/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 A beta(1-40). Our data suggest MIP-1 alpha and CCR5 as potential therapeutic targets for Alzheimer's disease treatment. (Am J Pathol 2009, 175:1586-1597; DOI: 10.2353/ajpath.2009.081113)