Polyamine biosynthesis dysregulation in Alzheimer’s disease and Down syndrome cellular models

ABSTRACT BACKGROUND Individuals with Down Syndrome (DS) frequently develop early onset Alzheimer’s 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. METHODS 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 Aβ42 aggregation and protein expression in DS fibroblasts. RESULTS Amyloid-β42 increased polyamine levels via ornithine decarboxylase (ODC) activation in a dose-dependent manner. DFMO reduced Aβ42 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 Aβ42 aggregates. CONCLUSION These findings suggest that polyamine biosynthesis may exacerbate Aβ42 toxicity and APP expression, contributing to AD progression in DS. The ability of DFMO to reduce Aβ42 aggregation and restore protein homeostasis presents the polyamine pathway as a therapeutic target for DS-AD management.