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Войти в исследования Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Age-related behavioral and molecular landmarks in new mouse models for studying Alzheimer's disease in Down syndrome.
СтатьяНазвание и аннотация: Перевод в очереди
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Baniowska Monika Rataj, Mumford Paige, Prestia Francesca, Stephan Pauline, Beament Millie, Birling Marie-Christine, Lanzillotta Chiara, Ciafardini Letizia, Barone Eugenio, Lau Gloria, Chevalier Claire, Nahy Chadia, Messaddeq Nadia, Lestra Thais, Wu Yixing, Nalesso Valérie, Di Domenico Fabio, Wiseman Frances, Herault Yann
Аннотация
INTRODUCTION: Down syndrome (DS) is the leading genetic cause of intellectual disability and Alzheimer's disease (AD), with over 90% of individuals developing AD-related dementia (DSAD). The triplication of the APP gene on chromosome 21 drives early amyloid-β (Aβ) accumulation, but other Hsa21 genes also contribute to pathology. Current DSAD models are limited by species-specific Aβ differences.
METHODS: We developed and characterized two novel DSAD mouse models with partial humanization of Aβ.
RESULTS: 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 β-secretase, increasing CTF-β and altering Aβ dynamics. Aβ 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.
DISCUSSION: They offer valuable tools to investigate early DSAD mechanisms and therapeutic strategies, pending development of a fully humanized trisomic model.
METHODS: We developed and characterized two novel DSAD mouse models with partial humanization of Aβ.
RESULTS: 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 β-secretase, increasing CTF-β and altering Aβ dynamics. Aβ 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.
DISCUSSION: They offer valuable tools to investigate early DSAD mechanisms and therapeutic strategies, pending development of a fully humanized trisomic model.