Beta-Amyloid Impairs Reelin Signaling

Reelin is a signaling protein increasingly associated with the pathogenesis of Alzheimer's disease that relevantly modulates tau phosphorylation. We have previously demonstrated that beta-amyloid peptide (A beta) alters reelin expression. We have now attempted to determine whether abnormal reelin triggered by A beta will result in signaling malfunction, contributing to the pathogenic process. Here, we show that reelin forms induced by beta-amyloid are less capable of down-regulating tau phosphorylation via disabled-1 and GSK3 beta kinase. We also demonstrate that the scaffold protein 14-3-3 that increases tau phosphorylation by modulating GSK3 beta activity, is up-regulated during defective reelin signaling. Binding of reelin to its receptor, mainly ApoER2 in the brain, relays the signal into the cell. We associate the impaired reelin signaling with inefficiency of reelin in forming active homodimers and decreased ability to bind efficiently to its receptor, ApoER2. More remarkably, reelin from Alzheimer cortex shows a tendency to form large complexes instead of homodimers, the active form for signaling. Our results suggest that reelin expression is altered by A beta leading to impaired reelin signaling.