UNRAVELING AGE-DEPENDENT BEHAVIORAL AND MOLECULAR FEATURES IN NOVEL MOUSE MODELS OF ALZHEIMER’S DISEASE IN DOWN SYNDROME: IMPLICATIONS FOR PATHOGENESIS AND TARGET IDENTIFICATION

Down syndrome (DS), the leading genetic cause of intellectual disability, is also associated with an exceptionally high risk of early-onset Alzheimer’s disease (AD), with over 90% of individuals developing AD-related dementia (DSAD). While triplication of the APP gene on chromosome 21 drives accelerated amyloid-β (Aβ) accumulation, the contributions of other Hsa21 genes to neurodevelopmental and neurodegenerative processes remain poorly understood. Existing DSAD models are further limited by species-specific differences in the Aβ sequence, impeding faithful recapitulation of human pathology.

To address these challenges, we developed and characterized two novel DSAD mouse models incorporating partial humanization of Aβ. Through comprehensive behavioral, cognitive, and molecular analyses, we demonstrate that these models recapitulate key early features of AD, including progressive cognitive impairment, hyperactivity, altered novelty and risk responses, tau hyperphosphorylation, and endolysosomal dysfunction. Mechanistically, we observed a shift in APP processing toward the β-secretase pathway, resulting in elevated CTF-β levels and dysregulated Aβ dynamics. Strikingly, Aβ humanization modulated behavioral phenotypes, improving performance in specific cognitive tasks while exacerbating anxiety-related traits. Additionally, the presence of myelinosomes and impaired autophagic flux further aligns these models with human AD pathology.

Our findings highlight the complex interplay between trisomy, APP gene dosage, and Aβ sequence in driving DSAD progression. These models provide a powerful platform for dissecting early AD mechanisms in DS and evaluating targeted interventions, bridging a critical gap until the development of a fully humanized DSAD model with three copies of APP.