Chen Xu-Qiao, Zuo Xinxin, Becker Ann, Mante Michael, Florio Jazmin B, Jadhav Satish G, Albay Ricardo, Johnstone Aaron, Karachentsev Dmitry, Rissman Robert, Zhao Hien, Dowdy Steven F, Mobley William C
Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, California, USA.
Alzheimers Dement. 2025 May;21(5):e70022. doi: 10.1002/alz.70022.
Down syndrome (DS) markedly raises the risk of Alzheimer's disease (DS-AD). Our findings identified widespread dysregulation of the endolysosomal network (ELN) in DS and DS-AD brains, driven by increased APP gene dose, hyperactivation of RAB5, and elevated levels of guanine nucleotide exchange factors (GEFs) for RABs 7 and 11.
We investigated whether increasing APP gene dose and RAB5 hyperactivation contributed to neuropathogenesis and whether a clinically feasible intervention could reverse ELN changes. The Dp16 DS-AD mouse model was treated with a mouse App-specific antisense oligonucleotide (App-ASO) and Rab5-specific ASOs targeting Rab5a and Rab5b.
App-ASO treatment normalized full-length APP (fl-APP) and its products, RAB5 activity, and downstream RABs 7 and 11 pathways. Rab5-ASOs reduced RAB5 levels and restored endosomal Rab activity. Both ASO treatments mitigated DS-AD-linked pathologies.
These findings highlight ELN dysregulation in DS and the therapeutic potential of ASO-based strategies targeting APP or Rab5 to counteract DS-AD features.
App-ASO treatment reduced the levels of APP and its products and normalized endosomal Rab activity and GEF levels in Dp16 mice. Administration of Rab5-ASOs reduced RAB5 levels and normalized endosomal Rab activity and GEF levels in Dp16 mice. Both ASO treatments were well tolerated and mitigated APP-linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, and synaptic protein loss. App-ASO or Rab5-ASOs reversed established pathological phenotypes in Dp16 mice.
唐氏综合征（DS）显著增加了患阿尔茨海默病（DS-AD）的风险。我们的研究结果表明，在DS和DS-AD大脑中，内溶酶体网络（ELN）存在广泛的失调，这是由APP基因剂量增加、RAB5过度激活以及RAB7和RAB11的鸟嘌呤核苷酸交换因子（GEF）水平升高所驱动的。
我们研究了增加APP基因剂量和RAB5过度激活是否导致神经病理发生，以及一种临床可行的干预措施是否能逆转ELN变化。用针对小鼠App的特异性反义寡核苷酸（App-ASO）和靶向Rab5a和Rab5b的Rab5特异性反义寡核苷酸治疗Dp16 DS-AD小鼠模型。
App-ASO治疗使全长APP（fl-APP）及其产物、RAB5活性以及下游RAB7和RAB11通路恢复正常。Rab5反义寡核苷酸降低了RAB5水平并恢复了内体Rab活性。两种反义寡核苷酸治疗均减轻了与DS-AD相关的病理变化。
这些发现突出了DS中ELN的失调以及基于反义寡核苷酸靶向APP或Rab5以对抗DS-AD特征的治疗潜力。
App-ASO治疗降低了Dp16小鼠中APP及其产物的水平，并使内体Rab活性和GEF水平恢复正常。给予Rab5反义寡核苷酸降低了Dp16小鼠中的RAB5水平，并使内体Rab活性和GEF水平恢复正常。两种反义寡核苷酸治疗耐受性良好，并减轻了与APP相关的病理变化，包括tau过度磷酸化、神经营养因子信号缺陷和突触蛋白丢失。App-ASO或Rab5反义寡核苷酸逆转了Dp16小鼠中已确立的病理表型。
