Amyloid-β oligomers stimulate microglia through a tyrosine kinase dependent mechanism

Alzheimer's disease (AD) has been well characterized by the presence of reactive microglia, often associated with beta-amyloid (A beta)plaque deposition. The oligomeric form of A beta peptide (A beta(o)) has neurotoxic effects in the presence of microglia and is suggested to potentiate proinflammatory changes in microglia in AD. Primary murine microglia cultures stimulated with A beta(o) displayed increased protein phosphotyrosine and secreted tumor necrosis factor (TNF)-alpha levels which were attenuated by the Src/Abl inhibitor, dasatinib. Intracerebroventricular infusions of A beta(o) into C57BL6/J mice stimulated increased microgliosis and protein phosphotyrosine levels that were also attenuated by dasatinib administration. The rodent findings were validated in human AD brains versus age-matched controls demonstrating reactive microglial association with A beta(o) deposits and increased microglial protein phosphotyrosine and phospho-Src levels. These data suggest a role for A beta(o) in microglial activation through a tyrosine kinase-dependant pathway both in rodent models and human disease. Use of a selective nonreceptor tyrosine kinase inhibitor such as dasatinib to attenuate microglial-dependent proinflammatory changes may prove to be an important step toward developing anti-inflammatory treatments for AD. (c) 2012 Elsevier Inc. All rights reserved.