Beta-Amyloid Impairs Reelin Signaling.docVIP

Beta-Amyloid Impairs Reelin Signaling Inmaculada Cuchillo-Ibá?ez , Valeria Balmaceda , Arancha Botella-López , Alberto Rabano , Jesus 1,2 1,2 1,2 2,3 , Javier Sáez-Valero Avila 2,4 1,2* 1 Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Sant Joan d’Alacant, Alicante, Spain, 2 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain, 3 Banco de Tejidos de la Fundación CIEN, CIEN Foundation, Carlos III Institute of Health, Alzheimer Center Reina Sofia Foundation, Madrid, Spain, 4 Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Consejo Superior de Investigaciones Científicas, Cantoblanco, Madrid, Spain Abstract 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 Alzhe