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 β-amyloid peptide (Aβ) alters reelin expression. We have now attempted to determine whether abnormal reelin triggered by Aβ will result in signaling malfunction, contributing to the pathogenic process. Here, we show that reelin forms induced by β-amyloid are less capable of down-regulating tau phosphorylation via disabled-1 and GSK3β kinase. We also demonstrate that the scaffold protein 14-3-3 that increases tau phosphorylation by modulating GSK3β 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 Aβ leading to impaired reelin signaling.
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Sant Joan d'Alacant, Alicante, Spain.
Inmaculada
I
Cuchillo-Ibáñez
Valeria
V
Balmaceda
Arancha
A
Botella-López
Alberto
A
Rabano
Jesus
J
Avila
Javier
J
Sáez-Valero
D048948:14-3-3 Proteins / Q000378:metabolism; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism
D048948:14-3-3 Proteins; D016229:Amyloid beta-Peptides; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; D016875:tau Proteins; C000717127:RELN protein, human; D012697:Serine Endopeptidases