{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T10:16:53Z","timestamp":1792059413177,"version":"4.4.0"},"reference-count":29,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,7,26]],"date-time":"2022-07-26T00:00:00Z","timestamp":1658793600000},"content-version":"vor","delay-in-days":206,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG055707"],"award-info":[{"award-number":["AG055707"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG056689"],"award-info":[{"award-number":["AG056689"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;D Transl Res &amp; Clin Interv"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Retromer complex proteins are decreased in Down syndrome (DS) brains and correlate inversely with brain amyloidosis. However, whether retromer dysfunction contributes to the amyloid beta (A\u03b2) and tau neuropathology of DS remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human trisomic induced Pluripotent Stem Cells (iPSCs) and isogenic controls were differentiated into forebrain neurons, and changes in retromer proteins, tau phosphorylated epitopes, and A\u03b2 levels were assessed in euploid and trisomic neurons using western blot and enzyme\u2010linked immunosorbent assay (ELISA). Genetic overexpression and pharmacological retromer stabilization were used to determine the functional role of the retromer complex system in modulating amyloid and tau pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Trisomic neurons developed age\u2010dependent retromer core protein deficiency associated with accumulation of A\u03b2 peptides and phosphorylated tau isoforms. Enhancing retromer function through overexpression or pharmacological retromer stabilization reduced amyloid and tau pathology in trisomic neurons. However, the effect was greater using a pharmacological approach, suggesting that targeting the complex stability may be more effective in addressing this neuropathology in DS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our results demonstrate that the retromer complex is directly involved in the development of the neuropathologic phenotype in DS, and that pharmacological stabilization of the complex should be considered as a novel therapeutic tool in people with DS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.12334","type":"journal-article","created":{"date-parts":[[2022,7,26]],"date-time":"2022-07-26T16:49:29Z","timestamp":1658854169000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndrome"],"prefix":"10.1002","volume":"8","author":[{"given":"Mary Elizabeth","family":"Curtis","sequence":"first","affiliation":[{"name":"Alzheimer's Center at Temple Lewis Katz School of Medicine Temple University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Smith","sequence":"additional","affiliation":[{"name":"Alzheimer's Center at Temple Lewis Katz School of Medicine Temple University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin E.","family":"Blass","sequence":"additional","affiliation":[{"name":"School of Pharmacy Temple University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Pratic\u00f2","sequence":"additional","affiliation":[{"name":"Alzheimer's Center at Temple Lewis Katz School of Medicine Temple University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,26]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12112"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/jir.12390"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/jir.12074"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1989.00520440031017"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2018.3616"},{"key":"e_1_2_8_7_1","first-page":"353","article-title":"Alzheimer's disease in down syndrome","volume":"1","author":"Head E","year":"2012","journal-title":"Eur J Neurodegener Dis"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy159"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-018-0221-3"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20667"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110182"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-019-0364-x"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0350-4"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25752"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26321"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1216575110"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-019-0489-y"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1508"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.04.020"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.06.008"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17524-7"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a016774"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26042"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-210701"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.02.018"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.03.020"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-019-0453-x"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2018.09.003"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201105109"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2018.01.031"}],"container-title":["Alzheimer's &amp; 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