Thirumalai Srishruthi, Livesey Frederick J, Patani Rickie, Hung Christy
UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, London, UK.
Talisman Therapeutics, Babraham Research Campus, Cambridge, UK.
Alzheimers Dement. 2025 Jan;21(1):e14560. doi: 10.1002/alz.14560.
Antisense oligonucleotides (ASOs) have shown promise in reducing amyloid precursor protein (APP) levels in neurons, but their effects in astrocytes, key contributors to neurodegenerative diseases, remain unclear. This study evaluates the efficacy of APP ASOs in astrocytes derived from an individual with Down syndrome (DS), a population at high risk for Alzheimer's disease (AD).
Human induced pluripotent stem cells (hiPSCs) from a healthy individual and an individual with DS were differentiated into astrocytes. Astrocytes were treated with APP ASOs for 10 days, and APP levels were quantified. Mitochondrial morphology and superoxide production in DS astrocytes were analyzed using super-resolution and confocal microscopy.
APP ASOs significantly reduced APP levels in astrocytes from both control and DS individuals. In DS astrocytes, treatment restored mitochondrial health, increasing mitochondrial number and size while reducing superoxide production.
APP ASOs effectively reduce APP levels and improve mitochondrial health in astrocytes, suggesting their potential as a therapeutic approach for DS and DS-related AD. Further in vivo studies are required to confirm these findings.
APP ASOs reduce APP levels in human iPSC-derived astrocytes. APP ASO treatment rescues mitochondrial phenotypes in trisomy 21 astrocytes. This study supports ASOs as a potential therapy for Down syndrome-related Alzheimer's disease.
反义寡核苷酸（ASO）已显示出在降低神经元中淀粉样前体蛋白（APP）水平方面的前景，但其在神经退行性疾病的关键促成因素星形胶质细胞中的作用仍不清楚。本研究评估了APP反义寡核苷酸在源自唐氏综合征（DS）个体的星形胶质细胞中的疗效，唐氏综合征个体是患阿尔茨海默病（AD）的高危人群。
将来自健康个体和唐氏综合征个体的人诱导多能干细胞（hiPSC）分化为星形胶质细胞。用APP反义寡核苷酸处理星形胶质细胞10天，并对APP水平进行定量。使用超分辨率和共聚焦显微镜分析唐氏综合征星形胶质细胞中的线粒体形态和超氧化物产生。
APP反义寡核苷酸显著降低了对照个体和唐氏综合征个体星形胶质细胞中的APP水平。在唐氏综合征星形胶质细胞中，治疗恢复了线粒体健康，增加了线粒体数量和大小，同时减少了超氧化物产生。
APP反义寡核苷酸有效降低星形胶质细胞中的APP水平并改善线粒体健康，表明它们作为唐氏综合征和唐氏综合征相关阿尔茨海默病治疗方法的潜力。需要进一步的体内研究来证实这些发现。
APP反义寡核苷酸降低人诱导多能干细胞来源的星形胶质细胞中的APP水平。APP反义寡核苷酸治疗挽救了21三体星形胶质细胞中的线粒体表型。本研究支持反义寡核苷酸作为唐氏综合征相关阿尔茨海默病的潜在治疗方法。
