{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:30:47Z","timestamp":1768519847313,"version":"3.49.0"},"posted":{"date-parts":[[2025,2,1]]},"group-title":"Biochemistry","reference-count":67,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>Individuals with Down Syndrome (DS) frequently develop early onset Alzheimer\u2019s disease (AD) with pathological hallmarks closely resembling AD due to several triplicated genes on chromosome 21. Polyamines are small, organic molecules that play a pivotal role for growth and differentiation, and a dysregulation of polyamine pathways is implicated in AD pathology. However, their role in DS-associated AD is unclear.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>We analyzed polyamines and their metabolite levels in mouse hippocampal cells and human DS-AD and AD hippocampal tissue and assessed the effects of the ODC inhibitor difluoromethylornithine (DFMO) on A\u03b242 aggregation and protein expression in DS fibroblasts.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>Amyloid-\u03b242 increased polyamine levels via ornithine decarboxylase (ODC) activation in a dose-dependent manner. DFMO reduced A\u03b242 aggregation, decreased amyloid precursor protein (APP) levels, and normalized proteins linked to AD pathology in DS fibroblasts. Polyamine levels were elevated in DS-AD hippocampal tissue, with colocalization of ODC and A\u03b242 aggregates.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSION<\/jats:title>\n                  <jats:p>These findings suggest that polyamine biosynthesis may exacerbate A\u03b242 toxicity and APP expression, contributing to AD progression in DS. The ability of DFMO to reduce A\u03b242 aggregation and restore protein homeostasis presents the polyamine pathway as a therapeutic target for DS-AD management.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.31.635912","type":"posted-content","created":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T22:47:38Z","timestamp":1738450058000},"source":"Crossref","is-referenced-by-count":0,"title":["Polyamine biosynthesis dysregulation in Alzheimer\u2019s disease and Down syndrome cellular 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