Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 24, Issue 3, Pages 493-501Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2009.12.003
Keywords
Alzheimer's disease; beta-Amyloid; Phosphomositide 3-kinase gamma; Microglia; Astrocyte; AS605240; Inflammation; Cytokine Brain; Cognitive decline
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Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- Programa de Apoio aos Nucleos de Excelencia (PRONEX)
- Fundacao de Apoio a Pesquisa do Estado de Santa Catarina (FAPESC)
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Alzheimer disease (AD) is the most common form of dementia in the elderly, and the neuro-pathological hallmarks of AD include neurofibrillary tangles (NFT), and deposition of beta-amyloid (A beta) in extracellular plaques. In addition, chronic inflammation due to recruitment of activated glial cells to amyloid plaques are an invariant component in AD, and several studies have reported that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may provide a measure of protection against AD. In this report we have investigated whether phosphoinositide 3-kinase gamma (PI3K gamma), which is important in inflammatory cell migration, plays a critical role in the neuro-inflammation, synaptic dysfunction, and cognitive deficits induced by intracerebroventricular injection of A beta(1-40) in mice. We found that the selective inhibitor of PI3K gamma, AS605240, was able to attenuate the A beta(1-40)-induced accumulation of activated astrocytes and microglia in the hippocampus, and decrease immuno-staining for p-Akt and cyclooxygenase-2 (COX-2). Interestingly, A beta(1-40) activated macrophages treated with AS605240 or another PI3K gamma inhibitor, AS252424, displayed impaired chemotaxis in vitro, but their expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) was unaffected. Finally, AS605240 prevented A beta(1-40)-induced cognitive deficits and synaptic dysfunction, but failed to modify scopolamine-induced amnesia. Our data suggests that inhibition of PI3K gamma may represent a novel therapeutic target for treating AD patients. (C) 2009 Elsevier Inc. All rights reserved.
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