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The Shugoshin 1 (Sgo1<jats:sup>\u2212\/+<\/jats:sup>) mouse model, a model for mitotic cohesinopathy\u2010genomic instability that is observed in human AD at a higher rate, showed spontaneous accumulation of amyloid\u2010\u03b2 in the brain at old age. With the model, novel insights into the molecular mechanism of LOAD development are anticipated. In this study, the initial appearance of cerebral amyloid\u2010\u03b2 accumulation was determined as 15\u201018\u00a0months of age (late middle age) in the Sgo1<jats:sup>\u2212\/+<\/jats:sup> model. The amyloid\u2010\u03b2 accumulation was associated with unexpected GSK3\u03b1\/\u03b2 inactivation, Wnt signaling activation, and ARC\/Arg3.1 accumulation, suggesting involvement of both the GSK3\u2010Arc\/Arg3.1 axis and the GSK3\u2010Wnt axis. As observed in human AD brains, neuroinflammation with IFN\u2010\u03b3 expression occurred with amyloid\u2010\u03b2 accumulation and was pronounced in the aged (24\u2010month\u2010old) Sgo1<jats:sup>\u2212\/+<\/jats:sup> model mice. AD\u2010relevant protein panels (oxidative stress defense, mitochondrial energy metabolism, and \u03b2\u2010oxidation and peroxisome) analysis indicated (a) early increases in Pdk1 and Phb in middle\u2010aged Sgo1<jats:sup>\u2212\/+<\/jats:sup> brains, and (b) misregulations in 32 proteins among 130 proteins tested in old age. Thus, initial amyloid\u2010\u03b2 accumulation in the Sgo1<jats:sup>\u2212\/+<\/jats:sup> model is suggested to be triggered by GSK3 inactivation and the resulting Wnt activation and ARC\/Arg3.1 accumulation. The model displayed characteristics and affected pathways similar to those of human LOAD including neuroinflammation, demonstrating its potential as a study tool for the LOAD development mechanism and for preclinical AD drug research and development.<\/jats:p>","DOI":"10.1111\/acel.13221","type":"journal-article","created":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T22:09:53Z","timestamp":1598652593000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["GSK3\u2010ARC\/Arg3.1 and GSK3\u2010Wnt signaling axes trigger amyloid\u2010\u03b2 accumulation and neuroinflammation in middle\u2010aged Shugoshin 1 mice"],"prefix":"10.1111","volume":"19","author":[{"given":"Chinthalapally V.","family":"Rao","sequence":"first","affiliation":[{"name":"Hematology\/Oncology Section Department of Medicine Center for Cancer Prevention and Drug Development University of Oklahoma Health Sciences Center (OUHSC Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mudassir","family":"Farooqui","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Iowa Hospitals and Clinics Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avanish","family":"Madhavaram","sequence":"additional","affiliation":[{"name":"Biology\/Exercise and Sports Science University of North Carolina Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hematology\/Oncology Section Department of Medicine Center for Cancer Prevention and Drug Development University of Oklahoma Health Sciences Center (OUHSC Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam S.","family":"Asch","sequence":"additional","affiliation":[{"name":"Hematology\/Oncology Section Department of Medicine Stephenson Cancer Center University of Oklahoma Health Sciences Center (OUHSC Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0536-5581","authenticated-orcid":false,"given":"Hiroshi Y.","family":"Yamada","sequence":"additional","affiliation":[{"name":"Hematology\/Oncology Section Department of Medicine Center for Cancer Prevention and Drug Development University of Oklahoma Health Sciences Center (OUHSC Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,8,28]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R116.746032"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2016.03.007"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.409250"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2015.05.010"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25432"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/1567205013666151221145445"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2013.0085"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2013.10.007"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.100801"},{"key":"e_1_2_11_11_1","volume-title":"The end of Alzheimer's: The first program to prevent and reverse cognitive decline","author":"Bredesen D. 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