Extracellular Amyloid β-protein (1-42) Oligomers Anchor Brain Cells and Make them inert as an Unconventional Integrin-Coupled Ligand.

This study aimed to investigate the effect of extracellular Aβ42 on neural cell migration, and the possible molecular mechanisms. Extracellular Aβ42 monomers did not negatively affect the motility of neural cells; however, they could promote cell migration from toxic extracellular Aβ42 oligomers. Contrastingly, extracellular Aβ42 aggregates, especially Aβ42 oligomers, significantly decreased neural cell migration while reducing their survival. Further, their soluble and deposited states showed different effects in causing the neural cells to become inert (incapable of moving). These findings were consistent with that of binding of Aβ42 oligomers to the plasma membrane or integrin receptors of the inert cells. By combining the protection of cell migratory capability by anti-oligomeric Aβ42 scFv antibody with the information obtained from our docking model of the Aβ42 trimer and integrin molecule, our findings suggest that extracellular Aβ42 aggregates disrupt the function of integrins mainly through the RHDS motif of Aβ42 chain, which eventually causes neural cells to become inert. Thus, we propose an "anchor" opinion, where Aβ42 aggregates in the ECM serve as the adverse "anchors" in the brain for anchoring neurons and for making neural cells inert, which causes their dysfunction. The neural cells with damaged motility could be restored or repaired if these anchoring effects of extracellular Aβ42 aggregates on the neural cells were severed or reduced, even if the "anchors" themselves were not completely eliminated. Medicines targeting soluble and deposited anchors of Aβ42 aggregates could be developed into effective treatments for Alzheimer disease.