α₁ Integrin Activation: A Link between β-Amyloid Deposition and Neuronal Death in Aging Hippocampal Neurons

A growing body of evidence obtained using in vitro model systems indicates that the deposition of fibrillar β-amyloid (AP) results in neurite degeneration and cell death in central neurons. Little is known, however, about the molecular mechanisms underlying these neurotoxic effects. We have shown previously that fibrillar Aβ induced sustained activation of the mitogen-activated protein kinase (MAPK) followed by hyperphosphorylation of tau proteins in aging hippocampal neurons. Furthermore, the blockage of MAPK activation using specific inhibitors prevented neurite degeneration in these cells. These results suggested that the MAPK signal transduction pathway could play a key role in Aβ-induced neurite degeneration. We sought to identify upstream elements of the MAPK signaling cascade activated by Aβ deposition. We evaluated the participation of the integrins in this pathway by monitoring the activation of MAPK in the presence of specific integrin inhibitors. Our results indicate that pretreatment of mature hippocampal neurons with either echistatin or α₁ integrin-blocking antibodies prevented Aβ-induced MAPK activation. In addition, the blockage of α ₁ activation prevented cell death induced by Aβ. Similar results were obtained when α₁ and β₁ integrin blocking antibodies were used combined. Taken collectively, these results identify α₁ integrin and the α₁ plus β₁ integrin complexes as potential targets for therapeutic intervention in the Aβ signaling pathway in aging neurons.