Role of the Macrophage Inflammatory Protein-1{alpha}/CC Chemokine Receptor 5 Signaling Pathway in the Neuroinflammatory Response and Cognitive Deficits Induced by {beta}-Amyloid Peptide

摘要

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-1 (MIP-1–/–)- or CC-chemokine receptor 5 (CCR5–/–)-deficient mice to address the role played by chemokines in molecular and behavioral alterations induced by Aβ_1–40. Aβ_1–40 induced a time-dependent increase of MIP-1 mRNA followed by accumulation of activated glial cells in the hippocampus of wild-type mice. MIP-1–/– and CCR5–/– mice displayed reduced astrocytosis and microgliosis in the hippocampus after Aβ_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-B, activator protein-1 and cyclic AMP response element-binding protein. Furthermore, MIP-1–/– and CCR5–/– macrophages showed impaired chemotaxis in vitro, although cytokine production in response to Aβ_1–40 was unaffected. Notably, the cognitive deficits and synaptic dysfunction induced by Aβ_1–40 were also attenuated in MIP-1–/– and CCR5–/– mice. Collectively, these results indicate that the MIP-1/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 Aβ_1–40. Our data suggest MIP-1 and CCR5 as potential therapeutic targets for Alzheimer’s disease treatment.