alpha1 Integrin activation: a link between beta-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 beta-amyloid (Abeta) 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 Abeta 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 Abeta-induced neurite degeneration. We sought to identify upstream elements of the MAPK signaling cascade activated by Abeta 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 alpha(1) integrin-blocking antibodies prevented Abeta-induced MAPK activation. In addition, the blockage of alpha(1) activation prevented cell death induced by Abeta. Similar results were obtained when alpha(1) and beta(1) integrin blocking antibodies were used combined. Taken collectively, these results identify alpha(1) integrin and the alpha(1) plus beta(1) integrin complexes as potential targets for therapeutic intervention in the Abeta signaling pathway in aging neurons.
Institute for Neuroscience, Northwestern University, Chicago, Illinois 60611, USA.
Kelsi L
KL
Anderson
Adriana
A
Ferreira
D000375:Aging / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D039423:Integrin alpha1 / Q000187:drug effects / Q000378:metabolism*; D039222:Integrin alpha1beta1 / Q000187:drug effects / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009454:Neurofibrils / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D039423:Integrin alpha1; D039222:Integrin alpha1beta1; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C057986:echistatin; D020928:Mitogen-Activated Protein Kinases