Acetylcholinesterase-amyloid-beta-peptide interaction and Wnt signaling involvement in Abeta neurotoxicity.
Previous studies have indicated that acetylcholinesterase (AChE) promotes amyloid-beta-peptide (Abeta) fibril formation and AChE-Abeta complexes increase Abeta-dependent neurotoxicity. Here we present evidence for the: i) identification of the AChE motif that promotes amyloid formation, ii) in vivo effect of AChE on brain plaque formation, and iii) connection between AChE-Abeta neurotoxicity and the Wnt signal transduction pathway. Computer modeling, stereotaxic infusions and cell biological techniques were used to study the above problems. Results indicated that a 3.4 kDa AChE peptide promotes Abeta fibril formation. AChE infusion into rat hippocampus determines the appearance of anti-Abeta and thioflavine-S positive plaques, and AChE-Abeta toxicity on hippocampal cultures was blocked by lithium, an activator of the Wnt cascade. We suggest that AChE-Abeta/Abeta dependent neurotoxicity may result in loss of function of Wnt signaling components, and open the possibility that lithium may be considered as a candidate for therapeutic intervention in Alzheimer's disease pathology.
Inestrosa
N C
NC
Centro de Regulación Celular y Patología, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile. ninestr@genes.bio.puc.cl
Alvarez
A
A
Godoy
J
J
Reyes
A
A
De Ferrari
G V
GV
D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D003198:Computer Simulation; D006624:Hippocampus / Q000473:pathology; D008297:Male; D009454:Neurofibrils / Q000473:pathology; D058225:Plaque, Amyloid / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051153:Wnt Proteins; D029961:Zebrafish Proteins
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D000110:Acetylcholinesterase