Involvement of phosphoinositide 3-kinase γ in the neuro-inflammatory response and cognitive impairments induced by β-amyloid 1–40 peptide in mice

https://doi.org/10.1016/j.bbi.2009.12.003Get rights and content
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Abstract

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 β-amyloid (Aβ) 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 γ (PI3Kγ), 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 Aβ1–40 in mice. We found that the selective inhibitor of PI3Kγ, AS605240, was able to attenuate the Aβ1–40-induced accumulation of activated astrocytes and microglia in the hippocampus, and decrease immuno-staining for p-Akt and cyclooxygenase-2 (COX-2). Interestingly, Aβ1–40 activated macrophages treated with AS605240 or another PI3Kγ inhibitor, AS252424, displayed impaired chemotaxis in vitro, but their expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was unaffected. Finally, AS605240 prevented Aβ1–40-induced cognitive deficits and synaptic dysfunction, but failed to modify scopolamine-induced amnesia. Our data suggests that inhibition of PI3Kγ may represent a novel therapeutic target for treating AD patients.

Keywords

Alzheimer’s disease
β-Amyloid
Phosphoinositide 3-kinase γ
Microglia
Astrocyte
AS605240
Inflammation
Cytokine
Brain
Cognitive decline

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