Araya Paula, Niemeyer Brian, Schade Kyndal, Dunn Lauren N, Waugh Katherine, Busquet Nicolas, Brindley Connie, Brown Chrisstopher, Winkler Caitlin, Lyford Hannah R, Britton Eleanor C, Ludwig Michael, Siegenthaler Julie, Galbraith Matthew D, Espinosa Joaquin M, Sullivan Kelly D
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
iScience. 2025 Jul 16;28(8):113130. doi: 10.1016/j.isci.2025.113130. eCollection 2025 Aug 15.
Individuals with Down syndrome (DS), caused by trisomy of chromosome 21 (chr21, T21), are strongly predisposed to Alzheimer's disease (AD), due to triplication of the gene, with ∼100% penetrance of AD brain pathology by age 40 and variable onset of dementia thereafter. It remains unclear what role other triplicated genes play in the pathophysiology of DS-associated AD (DS-AD). Using mouse models of DS-AD, we demonstrate that triplication of other chr21 genes has paradoxical effects on learning and memory in DS-AD mice, exacerbating some phenotypes and attenuating others. Spatial transcriptomic analysis revealed genome-wide alterations typified by upregulation of interferon (IFN) signatures and elevated levels of disease-associated microglia with concomitant decreases in neurons in DS-AD animals. Finally, systemic treatment with a JAK inhibitor improved cognition and rescued gene expression changes in DS-AD animals, indicating that IFN may be a driver of pathophysiology in DS-AD that could be amenable to therapeutic intervention.
唐氏综合征（DS）由21号染色体三体性（chr21，T21）引起，由于该基因的三倍体化，患阿尔茨海默病（AD）的风险极高，到40岁时AD脑病理的发生率约为100%，此后痴呆症发病时间不一。目前尚不清楚其他三倍体基因在唐氏综合征相关AD（DS-AD）的病理生理学中起什么作用。使用DS-AD小鼠模型，我们证明其他chr21基因的三倍体化对DS-AD小鼠的学习和记忆有矛盾的影响，加剧了一些表型，同时减轻了另一些表型。空间转录组分析揭示了全基因组改变，其特征是DS-AD动物中干扰素（IFN）特征上调、疾病相关小胶质细胞水平升高，同时神经元数量减少。最后，用JAK抑制剂进行全身治疗改善了DS-AD动物的认知能力，并挽救了基因表达变化，表明IFN可能是DS-AD病理生理学的驱动因素，可能适合进行治疗干预。
