Acetylcholinesterase (AChE)--amyloid-beta-peptide complexes in Alzheimer's disease. the Wnt signaling pathway.
Alzheimer's disease (AD) is characterized by selective neuronal cell death, which is probably caused by amyloid beta-peptide (Abeta) oligomers and fibrils. We have found that acetylcholinesterase (AChE), a senile plaque component, increases amyloid fibril assembly with the formation of highly toxic complexes (Abeta-AChE). The neurotoxic effect induced by Abeta-AChE complexes was higher than that induced by the Abeta peptide alone as shown both in vitro (hippocampal neurons) and in vivo (rats injected with Abeta peptide in the dorsal hippocampus). Interestingly, treatment with Abeta-AChE complexes decreases the cytoplasmic beta-catenin level, a key component of Wnt signaling. Conversely, the activation of this signaling pathway by Wnt-3a promotes neuronal survival and rescues changes in Wnt components (activation or subcellular localization). Moreover Frzb-1, a Wnt antagonist reverses the Wnt-3a neuroprotection effect against Abeta neurotoxicity. Compounds that mimic the Wnt signaling or modulate the cross-talking with this pathway could be used as neuroprotective agents for therapeutic strategies in AD patients.
Inestrosa
Nibaldo C
NC
Centro FONDAP de Regulación Celular y Patología Joaquín V. Luco, MIFAB, Facultad de Ciencias Biológicas Pontificia Universidad Católica de Chile, Santiago, Chile. ninestr@genes.bio.puc.cl
Urra
Soledad
S
Colombres
Marcela
M
D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins
D016229:Amyloid beta-Peptides; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D000110:Acetylcholinesterase