RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Alzheimers Dement. 2024 Apr;20(4):2632-2652. doi: 10.1002/alz.13703. Epub 2024 Feb 20.
The most significant genetic risk factor for late-onset Alzheimer's disease (AD) is APOE4, with evidence for gain- and loss-of-function mechanisms. A clinical need remains for therapeutically relevant tools that potently modulate APOE expression.
We optimized small interfering RNAs (di-siRNA, GalNAc) to potently silence brain or liver Apoe and evaluated the impact of each pool of Apoe on pathology.
In adult 5xFAD mice, siRNAs targeting CNS Apoe efficiently silenced Apoe expression and reduced amyloid burden without affecting systemic cholesterol, confirming that potent silencing of brain Apoe is sufficient to slow disease progression. Mechanistically, silencing Apoe reduced APOE-rich amyloid cores and activated immune system responses.
These results establish siRNA-based modulation of Apoe as a viable therapeutic approach, highlight immune activation as a key pathway affected by Apoe modulation, and provide the technology to further evaluate the impact of APOE silencing on neurodegeneration.
载脂蛋白 E4（APOE4）是导致迟发性阿尔茨海默病（AD）的最重要遗传风险因素，其作用机制涉及获得性功能和丧失性功能。目前仍需要治疗相关的工具来有效调节 APOE 的表达。
我们优化了小干扰 RNA（di-siRNA、GalNAc），以有效沉默大脑或肝脏中的 Apoe，并评估了每组 Apoe 对病理的影响。
在成年 5xFAD 小鼠中，靶向中枢神经系统 Apoe 的 siRNA 可有效沉默 Apoe 表达并减少淀粉样蛋白负担，而不影响系统性胆固醇，这证实了强烈沉默大脑 Apoe 足以减缓疾病进展。从机制上讲，沉默 Apoe 减少了富含 APOE 的淀粉样核心并激活了免疫系统反应。
这些结果确立了基于 siRNA 的 Apoe 调节作为一种可行的治疗方法，强调了免疫激活是受 Apoe 调节影响的关键途径，并提供了技术进一步评估 APOE 沉默对神经退行性变的影响。
