Signal transduction during amyloid-beta-peptide neurotoxicity: role in Alzheimer disease.
Alzheimer's disease (AD) is a neurodegenerative disorder with progressive dementia accompanied by two main structural changes in the brain: intracellular protein deposits termed neurofibrillary tangles (NFT) and extracellular amyloid protein deposits surrounded by dystrophic neurites that constitutes the senile plaques. Currently, it is widely accepted that amyloid beta-peptide (A beta) metabolism disbalance is crucial for AD progression. A beta deposition may be enhanced by molecular chaperones, including metals like copper and proteins like acetylcholinesterase (AChE). At the neuronal level, several AD-related proteins interact with transducers of the Wnt/beta-catenin signaling pathway, including beta-catenin and glycogen synthase kinase 3 beta (GSK-3 beta) and both in vitro and in vivo studies suggest that Wnt/beta-catenin signaling is a target for A beta toxicity. Accordingly, activation of this signaling by lithium or Wnt ligands in AD-experimental animal models or in primary hippocampal neurons attenuate A beta neurotoxicity by recovering beta-catenin levels and Wnt-target gene expression of survival genes such as bcl-2. On the other hand, peroxisomal proliferator-activated receptor gamma (PPAR gamma) and muscarinic acetylcholine receptor (mAChR) agonists also activate Wnt/beta-catenin signaling and they have neuroprotective effects on hippocampal neurons. Our studies are consistent with the idea that a sustained loss of function of Wnt signaling components would trigger a series of events, determining the onset and development of AD and that modulation of this pathway through the activation of cross-talking signaling cascades should be considered as a possible therapeutic strategy for AD treatment.
Fuentealba
Rodrigo A
RA
Centro FONDAP de Regulación Celular y Patología Joaquín Luco, MIFAB, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Farias
Ginny
G
Scheu
Jessica
J
Bronfman
Miguel
M
Marzolo
María Paz
MP
Inestrosa
Nibaldo C
NC
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D051153:Wnt Proteins; D051176:beta Catenin
D016229:Amyloid beta-Peptides; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin