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The Wnt signaling pathway has several key functions in the adult brain and has been associated with <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content>, mainly as a neuroprotective factor against A\u03b2 toxicity and tau phosphorylation. However, dysfunction of Wnt\/\u03b2\u2010catenin signaling might also play a role in the onset and development of the disease. J20 <jats:styled-content style=\"fixed-case\">APP<\/jats:styled-content>swInd transgenic (Tg) mouse model of <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content> was treated i.p. with various Wnt signaling inhibitors for 10\u00a0weeks during pre\u2010symptomatic stages. Then, cognitive, biochemical and histochemical analyses were performed. Wnt signaling inhibitors induced severe changes in the hippocampus, including alterations in Wnt pathway components and loss of Wnt signaling function, severe cognitive deficits, increased tau phosphorylation and A\u03b2<jats:sub>1\u201342<\/jats:sub> peptide levels, decreased A\u03b242\/A\u03b240 ratio and A\u03b2<jats:sub>1\u201342<\/jats:sub> concentration in the cerebral spinal fluid, and high levels of soluble A\u03b2 species and synaptotoxic oligomers in the hippocampus, together with changes in the amount and size of senile plaques. More important, we also observed severe alterations in treated wild\u2010type (<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>) mice, including behavioral impairment, tau phosphorylation, increased A\u03b2<jats:sub>1\u201342<\/jats:sub> in the hippocampus, decreased A\u03b2<jats:sub>1\u201342<\/jats:sub> in the cerebral spinal fluid, and hippocampal dysfunction. Wnt inhibition accelerated the development of the pathology in a Tg <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content> mouse model and contributed to the development of Alzheimer's\u2010like changes in <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> mice. These results indicate that Wnt signaling plays important roles in the structure and function of the adult hippocampus and suggest that inhibition of the Wnt signaling pathway is an important factor in the pathogenesis of <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content>.<\/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\/jnc14278-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p><jats:bold>Read the Editorial Highlight for this article on page<\/jats:bold> <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.1111\/jnc.14276\">356<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14278","type":"journal-article","created":{"date-parts":[[2017,12,14]],"date-time":"2017-12-14T18:33:14Z","timestamp":1513276394000},"page":"443-465","source":"Crossref","is-referenced-by-count":82,"title":["Wnt signaling loss accelerates the appearance of neuropathological hallmarks of Alzheimer's disease in J20\u2010<scp>APP<\/scp> transgenic and wild\u2010type mice"],"prefix":"10.1111","volume":"144","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7084-0318","authenticated-orcid":false,"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 New South Wales 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":[[2018,1,26]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.13.3797"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.09.003"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2004.02.028"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.230302"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21902"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600251"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.npep.2015.06.008"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2008.96"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90400-6"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a007906"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5230-04.2005"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1381-04.2004"},{"key":"e_1_2_8_14_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.3233\/JAD-130230","article-title":"Tetrahydrohyperforin decreases cholinergic markers associated with amyloid\u2010\u03b2 plaques, 4\u2010hydroxynonenal formation, and caspase\u20103 activation in A\u03b2PP\/PS1 mice","volume":"36","author":"Carvajal F.","year":"2013","journal-title":"J. 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