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.
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.
Passos
Giselle Fazzioni
GF
Departamento de Farmacologia, Centro de Ciéncias Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
Figueiredo
Cláudia Pinto
CP
Prediger
Rui Daniel Schröder
RD
Pandolfo
Pablo
P
Duarte
Filipe Silveira
FS
Medeiros
Rodrigo
R
Calixto
João B
JB
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
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