amyloid-beta-peptides and Neuritis

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 (Abeta) 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 (PI3Kgamma), 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 Abeta(1-40) in mice. We found that the selective inhibitor of PI3Kgamma, AS605240, was able to attenuate the Abeta(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, Abeta(1-40) activated macrophages treated with AS605240 or another PI3Kgamma inhibitor, AS252424, displayed impaired chemotaxis in vitro, but their expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) was unaffected. Finally, AS605240 prevented Abeta(1-40)-induced cognitive deficits and synaptic dysfunction, but failed to modify scopolamine-induced amnesia. Our data suggests that inhibition of PI3Kgamma may represent a novel therapeutic target for treating AD patients.

Topics: Amyloid beta-Peptides; Animals; Cell Survival; Chemotaxis, Leukocyte; Class Ib Phosphatidylinositol 3-Kinase; Cognition; Cyclooxygenase 2; Enzyme Inhibitors; Image Processing, Computer-Assisted; Immunohistochemistry; Interleukin-1beta; Isoenzymes; Male; Maze Learning; Mice; Mice, Inbred C57BL; Neuritis; Neuroglia; Peptide Fragments; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Synapses; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD) is the commonest form of adult onset dementia and is characterised neuropathologically by the accumulation of plaques containing beta-amyloid (A beta) fibrils, reactive astrocytes, activated microglia, and leukocytes. A beta plays a role in the pathology of AD by directly causing neuronal cytotoxicity and stimulating microglia to secrete cytokines and reactive oxygen species (ROS) which also damage neurons. Here, we demonstrate that A beta activates astrocytes and oligodendrocytes (the most common cell types in the brain) to produce chemokines, in particular MCP-1 and RANTES, which serve as potent in vitro microglial and macrophage chemoattractants. Furthermore, we have shown that A beta activates astrocytes to upregulate pro-inflammatory cytokine expression and enhances the production of ROS. We propose therefore that A beta-mediated astrocyte activation initiates an inflammatory cascade which could be targeted for therapeutic intervention in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Brain; Chemokine CCL2; Chemokine CCL5; Chemokine CXCL2; Chemokines, CXC; Chemotactic Factors; Chemotaxis; Gene Expression; Growth Inhibitors; Growth Substances; Intercellular Signaling Peptides and Proteins; Macrophages; Microglia; Monokines; Neuritis; Oligodendroglia; Oligonucleotide Probes; Peptide Fragments; Rats; Rats, Wistar; Reactive Oxygen Species