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The triplication of the\n                      <jats:italic>APP<\/jats:italic>\n                      gene on chromosome 21 drives early amyloid\u2010\u03b2 (A\u03b2) accumulation, but other Hsa21 genes also contribute to pathology. Current DSAD models are limited by species\u2010specific A\u03b2 differences.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We developed and characterized two novel DSAD mouse models with partial humanization of A\u03b2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>These models exhibit early AD features: cognitive deficits, hyperactivity, altered novelty and risk responses, tau hyperphosphorylation, and endolysosomal dysfunction. Amyloid precursor protein (APP) processing shifts toward \u03b2\u2010secretase, increasing CTF\u2010\u03b2 and altering A\u03b2 dynamics. A\u03b2 humanization modulates behavior, improving specific cognitive tasks but enhancing anxiety traits. Myelinosome formation and impaired autophagic flux further align these models with human AD pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>They offer valuable tools to investigate early DSAD mechanisms and therapeutic strategies, pending development of a fully humanized trisomic model.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71498","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T03:41:37Z","timestamp":1779421297000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Age\u2010related behavioral and molecular landmarks in new mouse models for studying Alzheimer's disease in Down syndrome"],"prefix":"10.1002","volume":"22","author":[{"given":"Monika Rataj","family":"Baniowska","sequence":"first","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique Biologie Mol\u00e9culaire et Cellulaire, IGBMC, UMR 7104\u2010 UMR\u2010S 1258 Universit\u00e9 de Strasbourg, CNRS, Inserm  Illkirch France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige","family":"Mumford","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Prestia","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences A. 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