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According to the amyloid hypothesis, the amyloid\u2010\u03b2 (A\u03b2) peptide plays a key role in the pathogenesis of AD. A\u03b2 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 A\u03b2 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 A\u03b2<jats:sub>42<\/jats:sub> peptide, the A\u03b2<jats:sub>42<\/jats:sub>\/A\u03b2<jats:sub>40<\/jats:sub> ratio, and the levels of A\u03b2 oligomers such as trimers and tetramers. Moreover, we show that activating Wnt signaling reduces the levels of A\u03b2<jats:sub>42<\/jats:sub> and its aggregates, increases A\u03b2<jats:sub>40<\/jats:sub> levels, and reduces the A\u03b2<jats:sub>42<\/jats:sub>\/A\u03b2<jats:sub>40<\/jats:sub> ratio. Finally, we show that the protective effects observed in response to activation of the Wnt pathway rely on \u03b2\u2010catenin\u2010dependent transcription, which is demonstrated experimentally via the expression of various \u2018mutant forms of \u03b2\u2010catenin\u2019. Together, our findings indicate that loss of the Wnt signaling pathway may contribute to the pathogenesis of AD.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13873-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13873","type":"journal-article","created":{"date-parts":[[2016,10,25]],"date-time":"2016-10-25T08:02:49Z","timestamp":1477382569000},"page":"1175-1191","source":"Crossref","is-referenced-by-count":78,"title":["Inhibition of Wnt signaling induces amyloidogenic processing of amyloid precursor protein and the production and aggregation of Amyloid\u2010\u03b2 (A\u03b2)<sub>42<\/sub> peptides"],"prefix":"10.1111","volume":"139","author":[{"given":"Cheril","family":"Tapia\u2010Rojas","sequence":"first","affiliation":[{"name":"Centro de Envejecimiento y Regeneraci\u00f3n (CARE UC) Departamento de Biolog\u00eda Celular y Molecular Facultad de Ciencias Biol\u00f3gicas Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia V.","family":"Burgos","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Facultad de Medicina Universidad Austral de Chile Valdivia Chile"},{"name":"Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe) Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nibaldo C.","family":"Inestrosa","sequence":"additional","affiliation":[{"name":"Centro de Envejecimiento y Regeneraci\u00f3n (CARE UC) Departamento de Biolog\u00eda Celular y Molecular Facultad de Ciencias Biol\u00f3gicas Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"},{"name":"Centre for Healthy Brain Ageing School of Psychiatry Faculty of Medicine University of New South Wales Sydney Australia"},{"name":"Centro de Excelencia en Biomedicina de Magallanes (CEBIMA) Universidad de Magallanes Punta Arenas Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,12,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1201209109"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300825200"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1162844"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0083096"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1381-04.2004"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0136313"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1358\/dnp.2009.22.10.1443391"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2015.00186"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511920200"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04181.x"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.137"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.2174\/1871527312666131223113900"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2009.218"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13351"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0404875101"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(94)90360-3"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.27.19465"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.wnr.0000220137.06542.a0"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2006.11.036"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(09)63030-5"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1033.2003.03415.x"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.07.013"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2101"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2006-9S317"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/embo-reports\/kvf181"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08356"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2755"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-3-9"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjt051"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11481-012-9417-5"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2012.03.001"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2014.04.012"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10615"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1017033108"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4849-06.2007"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-0186(96)00119-2"},{"issue":"1","key":"e_1_2_8_38_1","first-page":"S49","article-title":"Synaptotoxic 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