title: Amyloid-β oligomers stimulate microglia through a tyrosine kinase dependent mechanism.
abstract: Alzheimer's disease (AD) has been well characterized by the presence of reactive microglia, often associated with β-amyloid (Aβ) plaque deposition. The oligomeric form of Aβ peptide (Aβ(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 Aβ(o) displayed increased protein phosphotyrosine and secreted tumor necrosis factor (TNF)-α levels which were attenuated by the Src/Abl inhibitor, dasatinib. Intracerebroventricular infusions of Aβ(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 Aβ(o) deposits and increased microglial protein phosphotyrosine and phospho-Src levels. These data suggest a role for Aβ(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.
authors: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58203, USA.
authors: Gunjan
authors: G
authors: Dhawan
authors: Angela M
authors: AM
authors: Floden
authors: Colin K
authors: CK
authors: Combs
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D000069439:Dasatinib; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D019000:Phosphotyrosine / Q000032:analysis; D058225:Plaque, Amyloid / Q000378:metabolism; D011108:Polymers / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D011108:Polymers; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D000069439:Dasatinib