Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia.
Alzheimer's disease (AD) is a devastating neurological disorder characterized by loss of cognitive skills and progressive dementia. The pathological hallmark of AD is the presence of numerous senile plaques throughout the hippocampus and cerebral cortex associated with degenerating axons, neurofibrillary tangles, and gliosis. The core of the senile plaque primarily is composed of the 39-43 amino acid beta-amyloid peptide (Abeta), which forms fibrils of beta-pleated sheets. Although considerable genetic evidence implicates Abeta in the pathogenesis of AD, a direct causal link remains to be established. Senile plaques are foci of local inflammatory processes, as evidenced by the presence of numerous activated microglia and acute phase proteins. Abeta has been shown to elicit inflammatory responses in microglia; however, the intracellular events mediating these effects are largely unknown. We report that exposure of microglia and THP1 monocytes to fibrillar Abeta led to time- and dose-dependent increases in protein tyrosine phosphorylation of a population of proteins similar to that elicited by classical immune stimuli such as immune complexes. The tyrosine kinases Lyn, Syk, and FAK were activated on exposure of microglia and THP1 monocytes to Abeta, resulting in the tyrosine kinase-dependent generation of superoxide radicals. The present data support a role for oxidative damage in the pathogenesis of AD, provide an important mechanistic link between Abeta and the generation of reactive oxygen intermediates, and identify molecular targets for therapeutic intervention in AD.
McDonald
D R
DR
Alzheimer Research Laboratory, Department of Neurology and Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Brunden
K R
KR
Landreth
G E
GE
D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000502:physiology; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D017628:Microglia / Q000502:physiology*; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology* / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017452:Receptors, IgG / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism*; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D017452:Receptors, IgG; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); D013481:Superoxides; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase