Fig. 9.

Aβ-stimulated microglial and monocytic proinflammatory products cause TNFα/iNOS-dependent neuronal apoptosis. Binding of Aβ fibrils to microglia initiates a tyrosine kinase-dependent signaling response involving Src family members and Syk as membrane proximal signaling elements. Src kinases, such as Lyn, mediate the activation of several tyrosine kinase activities associated with adhesion and phagocytosis of Aβ fibrils. In parallel, Syk kinase activity specifically regulates increased cytokine production in response to Aβ stimulation. A separate cytokine regulatory pathway using the proinflammatory transcription factor NFκB is also activated on Aβ stimulation to operate independent of Src and Syk activation. Aβ-stimulated microglia secrete TNFα plus an additional secretory factor(s) to produce neuronal apoptosis. The apoptosis requires iNOS activity and correlates with increased expression of iNOS and peroxynitrite.