title: WASP-1, a canonical Wnt signaling potentiator, rescues hippocampal synaptic impairments induced by Aβ oligomers.
abstract: Amyloid-β (Aβ) oligomers are a key factor in Alzheimer's disease (AD)-associated synaptic dysfunction. Aβ oligomers block the induction of hippocampal long-term potentiation (LTP) in rodents. The activation of Wnt signaling prevents Aβ oligomer-induced neurotoxic effects. The compound WASP-1 (Wnt-activating small molecule potentiator-1), has been described as a synergist of the ligand Wnt-3a, enhancing the activation of Wnt/β-catenin signaling. Herein, we report that WASP-1 administration successfully rescued Aβ-induced synaptic impairments both in vitro and in vivo. The activation of canonical Wnt/β-catenin signaling by WASP-1 increased synaptic transmission and rescued hippocampal LTP impairments induced by Aβ oligomers. Additionally, intra-hippocampal administration of WASP-1 to the double transgenic APPswe/PS1dE9 mouse model of AD prevented synaptic protein loss and reduced tau phosphorylation levels. Moreover, we found that WASP-1 blocked Aβ aggregation in vitro and reduced pathological tau phosphorylation in vivo. These results indicate that targeting canonical Wnt signaling with WASP-1 could have value for treating AD.
authors.affiliation: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
authors.forename: Jessica Y
authors.initials: JY
authors.lastname: Vargas
authors.affiliation: Centro de Neurobiología y Plasticidad Cerebral, Departamento de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
authors.forename: Juan
authors.initials: J
authors.lastname: Ahumada
authors.affiliation: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
authors.forename: Macarena S
authors.initials: MS
authors.lastname: Arrázola
authors.affiliation: Centro de Neurobiología y Plasticidad Cerebral, Departamento de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile. Electronic address: marco.fuenzalida@uv.cl.
authors.forename: Marco
authors.initials: M
authors.lastname: Fuenzalida
authors.affiliation: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, P. 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 de Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Puerto Montt, Chile. Electronic address: ninestrosa@bio.puc.cl.
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000627:therapeutic use*; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000627:therapeutic use*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013569:Synapses / Q000187:drug effects* / Q000235:genetics / Q000502:physiology / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011518:Proto-Oncogene Proteins
keywords: Alzheimer's disease; Aβ oligomers; Synaptic plasticity; Synaptic proteins; WASP-1; Wnt signaling