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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.

SUBMITTER: Passos GF

PROVIDER: S-EPMC2751555 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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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.

Passos Giselle Fazzioni GF Figueiredo Cláudia Pinto CP Prediger Rui Daniel Schröder RD Pandolfo Pablo P Duarte Filipe Silveira FS Medeiros Rodrigo R Calixto João B JB

The American journal of pathology 20090903 4

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 altera ...[more]

PMID: 19729478

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Project description:BackgroundEpidemiological data suggests statins could reduce the risk of dementia, and more specifically, Alzheimer's disease (AD). Pre-clinical data suggests statins reduce the risk of dementia through their pleiotropic effects rather than their cholesterol lowering effects. While AD is a leading cause of dementia, it is frequently found co-morbidly with cerebral small vessel disease and other vascular contributions to cognitive impairment and dementia (VCID), which are another leading cause of dementia. In this study, we determined if atorvastatin ameliorated hyperhomocysteinemia (HHcy)-induced VCID.MethodsWild-type (C57Bl6/J) mice were placed on a diet to induce HHcy or a control diet each with or without atorvastatin for 14 weeks. Mice underwent novel object recognition testing before tissue collection. Plasma total cholesterol and total homocysteine as well as related metabolites were measured. Using qPCR and NanoString technology, we profiled glial cell-associated gene expression changes. Finally, microglial morphology, astrocyte end feet, and microhemorrhages were analyzed using histological methods.ResultsAtorvastatin treatment of HHcy in mice led to no changes in total cholesterol but decreases in total homocysteine in plasma. While HHcy decreased expression of many glial genes, atorvastatin rescued these gene changes, which mostly occurred in oligodendrocytes and microglia. Microglia in HHcy mice with atorvastatin were trending towards fewer processes compared to control with atorvastatin, but there were no atorvastatin effects on astrocyte end feet. While atorvastatin treatment was trending towards increasing the area of microhemorrhages in HHcy mice in the frontal cortex, it only slightly (non-significantly) reduced the number of microhemorrhages. Finally, atorvastatin treatment in HHcy mice led to improved cognition on the novel object recognition task.ConclusionsThese data suggest that atorvastatin rescued cognitive changes induced by HHcy most likely through lowering plasma total homocysteine and rescuing gene expression changes rather than impacts on vascular integrity or microglial changes.

Dataset Information

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.

Publications

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.

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