title: Role of the macrophage inflammatory protein-1alpha/CC chemokine receptor 5 signaling pathway in the neuroinflammatory response and cognitive deficits induced by beta-amyloid peptide.
abstract: The hallmarks of Alzheimer's disease include the deposition of beta-amyloid (Abeta), 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-1alpha (MIP-1alpha(-/-))- or CC-chemokine receptor 5 (CCR5(-/-))-deficient mice to address the role played by chemokines in molecular and behavioral alterations induced by Abeta(1-40). Abeta(1-40) induced a time-dependent increase of MIP-1alpha mRNA followed by accumulation of activated glial cells in the hippocampus of wild-type mice. MIP-1alpha(-/-) and CCR5(-/-) mice displayed reduced astrocytosis and microgliosis in the hippocampus after Abeta(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-kappaB, activator protein-1 and cyclic AMP response element-binding protein. Furthermore, MIP-1alpha(-/-) and CCR5(-/-) macrophages showed impaired chemotaxis in vitro, although cytokine production in response to Abeta(1-40) was unaffected. Notably, the cognitive deficits and synaptic dysfunction induced by Abeta(1-40) were also attenuated in MIP-1alpha(-/-) and CCR5(-/-) mice. Collectively, these results indicate that the MIP-1alpha/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 Abeta(1-40). Our data suggest MIP-1alpha and CCR5 as potential therapeutic targets for Alzheimer's disease treatment.
authors.affiliation: Departamento de Farmacologia, Centro de Ciéncias Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: Giselle Fazzioni
authors.initials: GF
authors.lastname: Passos
authors.forename: Cláudia Pinto
authors.initials: CP
authors.lastname: Figueiredo
authors.forename: Rui Daniel Schröder
authors.initials: RD
authors.lastname: Prediger
authors.forename: Pablo
authors.initials: P
authors.lastname: Pandolfo
authors.forename: Filipe Silveira
authors.initials: FS
authors.lastname: Duarte
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Medeiros
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D054405:Chemokine CCL3 / Q000378:metabolism*; D003072:Cognition Disorders / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D017353:Gene Deletion; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009420:Nervous System / Q000187:drug effects / Q000473:pathology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D019713:Receptors, CCR5 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D054405:Chemokine CCL3; D010446:Peptide Fragments; D019713:Receptors, CCR5; D014157:Transcription Factors; C078592:amyloid beta-protein (1-40); D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2