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Our findings identified widespread dysregulation of the endolysosomal network (ELN) in DS and DS\u2010AD brains, driven by increased\n                      <jats:italic>APP<\/jats:italic>\n                      gene dose, hyperactivation of RAB5, and elevated levels of guanine nucleotide exchange factors (GEFs) for RABs 7 and 11.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We investigated whether increasing\n                      <jats:italic>APP<\/jats:italic>\n                      gene dose and RAB5 hyperactivation contributed to neuropathogenesis and whether a clinically feasible intervention could reverse ELN changes. The Dp16 DS\u2010AD mouse model was treated with a mouse\n                      <jats:italic>App<\/jats:italic>\n                      \u2010specific antisense oligonucleotide (\n                      <jats:italic>App<\/jats:italic>\n                      \u2010ASO) and\n                      <jats:italic>Rab5<\/jats:italic>\n                      \u2010specific ASOs targeting\n                      <jats:italic>Rab5a<\/jats:italic>\n                      and\n                      <jats:italic>Rab5b<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      <jats:italic>App<\/jats:italic>\n                      \u2010ASO treatment normalized full\u2010length APP (fl\u2010APP) and its products, RAB5 activity, and downstream RABs 7 and 11 pathways.\n                      <jats:italic>Rab5<\/jats:italic>\n                      \u2010ASOs reduced RAB5 levels and\u00a0restored endosomal Rab activity. Both ASO treatments mitigated DS\u2010AD\u2010linked pathologies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      These findings highlight ELN dysregulation in DS and the therapeutic potential of ASO\u2010based strategies targeting\n                      <jats:italic>APP<\/jats:italic>\n                      or\n                      <jats:italic>Rab5<\/jats:italic>\n                      to counteract DS\u2010AD features.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>App<\/jats:italic>\n                            \u2010ASO treatment reduced the levels of APP and its products and normalized endosomal Rab activity and GEF levels in Dp16 mice.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Administration of\n                            <jats:italic>Rab5<\/jats:italic>\n                            \u2010ASOs reduced RAB5 levels and normalized endosomal Rab activity and GEF levels in Dp16 mice.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Both ASO treatments were well tolerated and mitigated APP\u2010linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, and synaptic protein loss.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>App<\/jats:italic>\n                            \u2010ASO or\n                            <jats:italic>Rab5<\/jats:italic>\n                            \u2010ASOs reversed established pathological phenotypes in Dp16 mice.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70022","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T23:54:56Z","timestamp":1746662096000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Antisense oligonucleotides directed against\n                    <i>App<\/i>\n                    and\n                    <i>Rab5<\/i>\n                    \u00a0normalized endosomal Rab activity and reversed DS\u2010AD\u2010linked degenerative phenotypes in the Dp16 mouse model of Down syndrome"],"prefix":"10.1002","volume":"21","author":[{"given":"Xu\u2010Qiao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neurosciences University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Zuo","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Mante","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jazmin B.","family":"Florio","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish G.","family":"Jadhav","sequence":"additional","affiliation":[{"name":"Department of Cellular &amp; 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