Wnt signaling function in Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease with progressive de mentia accompanied by three main structural changes in the brain: diffuse l oss of neurons; intracellular protein deposits termed neurofibrillary tangl es (NFT) and extracellular protein deposits termed amyloid or senile plaque s, surrounded by dystrophic neurites. Two major hypotheses have been propos ed in order to explain the molecular hallmarks of the disease: The 'amyloid cascade' hypothesis and the 'neuronal cytoskeletal degeneration' hypothesi s. While the former is supported by genetic studies of the early-onset fami lial forms of AD (FAD), the latter revolves around the observation in vivo that cytoskeletal changes - including the abnormal phosphorylation state of the microtubule associated protein tau - may precede the deposition of sen ile plaques. Recent studies have suggested that the trafficking process of membrane associated proteins is modulated by the FAD-linked presenilin (PS) proteins, and that amyloid beta-peptide deposition may be initiated intrac ellularly, through the secretory pathway. Current hypotheses concerning pre senilin function are based upon its cellular localization and its putative interaction as macromolecular complexes with the cell-adhesion/signaling be ta-catenin molecule and the glycogen synthase kinase 3 beta (GSK-3 beta) en zyme. Developmental studies have shown that PS proteins function as compone nts in the Notch signal transduction cascade and that beta-catenin and GSK- S beta are transducers of the Wnt signaling pathway. Both pathways are thou ght to have an important role in brain development, and they have been conn ected through Dishevelled (Dvl) protein, a known transducer of the Wnt path way. In addition to a review of the current state of research on the subjec t, we present a cell signaling model in which a sustained loss of function of Wnt signaling components would trigger a series of misrecognition events , determining the onset and development of AD. (C) 2000 Elsevier Science B. V. All rights reserved.