title: Inhibition of Wnt signaling induces amyloidogenic processing of amyloid precursor protein and the production and aggregation of Amyloid-β (Aβ)42peptides.
abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder and the most frequent cause of dementia in the aged population. According to the amyloid hypothesis, the amyloid-β (Aβ) peptide plays a key role in the pathogenesis of AD. Aβ is generated from the amyloidogenic processing of amyloid precursor protein and can aggregate to form oligomers, which have been described as a major synaptotoxic agent in neurons. Dysfunction of Wnt signaling has been linked to increased Aβ formation; however, several other studies have argued against this possibility. Herein, we use multiple experimental approaches to confirm that the inhibition of Wnt signaling promoted the amyloidogenic proteolytic processing of amyloid precursor protein. We also demonstrate that inhibiting Wnt signaling increases the production of the Aβ42peptide, the Aβ42/Aβ40ratio, and the levels of Aβ oligomers such as trimers and tetramers. Moreover, we show that activating Wnt signaling reduces the levels of Aβ42and its aggregates, increases Aβ40levels, and reduces the Aβ42/Aβ40ratio. Finally, we show that the protective effects observed in response to activation of the Wnt pathway rely on β-catenin-dependent transcription, which is demonstrated experimentally via the expression of various 'mutant forms of β-catenin'. Together, our findings indicate that loss of the Wnt signaling pathway may contribute to the pathogenesis of AD.
authors: Centro de Envejecimiento y Regeneración (CARE UC), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Cheril
authors: C
authors: Tapia-Rojas
authors: Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile.|Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Sydney, Australia.
authors: Patricia V
authors: PV
authors: Burgos
authors: Centro de Envejecimiento y Regeneración (CARE UC), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.|Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia.|Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile.
authors: Nibaldo C
authors: NC
authors: Inestrosa
mesh_terms: D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004224:Diterpenes / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010446:Peptide Fragments / Q000096:biosynthesis*; D066329:Protein Aggregates / Q000187:drug effects / Q000502:physiology*; D051153:Wnt Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D000071818:Wnt-5a Protein / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004224:Diterpenes; D010446:Peptide Fragments; D066329:Protein Aggregates; C085389:WNT5A protein, human; C092778:WNT7A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C075222:amyloid beta-protein (1-42); C030419:andrographolide
keywords: 
  APP
  ; GSK-3β; Wnt signaling; Wnt target genes; Wnt/β-catenin; amyloid-β