Senescence Targeting Methods Impact Alzheimer's Disease Features in 3xTg Mice.

IF 3.4 3区医学 Q2 NEUROSCIENCES

Journal of Alzheimer's Disease Pub Date : 2024-01-01 DOI:10.3233/JAD-230465

Pei Y Ng, Cheng Zhang, Hu Li, Darren J Baker

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引用次数: 0

Abstract

Background: Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer's disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg).

Objective: To investigate the effects of senescent cell clearance in the 3xTg mouse model.

Methods: 3xTg mice were treated with senolytics (ABT263 (navitoclax; NAVI), a combination of dasatinib and quercetin (D+Q)), or subjected to transgene-mediated removal of p16-expressing cells (via INK-ATTAC).

Results: Senolytic treatments consistently reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation were attenuated with treatment. These beneficial effects were not observed with short-term senolytic treatment in mice with more advanced disease.

Conclusions: Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for the treatment of this debilitating disease.

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衰老靶向方法影响 3xTg 小鼠的阿尔茨海默病特征

背景：细胞衰老与神经退行性疾病有关，在研究阿尔茨海默病（AD）个别病因的小鼠模型中，利用基因或药物策略（衰老剂）清除衰老细胞已显示出有益的效果。然而，在同时表现出斑块和 tau 病理学的小鼠模型（3xTg）中，衰老细胞的清除是否会改变疾病状态仍不清楚：方法：用衰老剂（ABT263（navitoclax；NAVI）、达沙替尼和槲皮素的组合（D+Q））治疗 3xTg 小鼠，或通过转基因介导清除 p16 表达细胞（通过 INK-ATTAC）：结果：在3xTg小鼠中，衰老治疗可持续减少小胶质细胞增多，并改善淀粉样蛋白和tau病理学。通过 RNA 测序，我们发现有证据表明，治疗可减轻突触功能障碍和神经炎症。在对晚期疾病小鼠进行短期溶老治疗时，并没有观察到这些有益的影响：总之，我们的研究结果进一步证实了清除衰老细胞可对老年痴呆症产生有益影响，并强调了早期干预对治疗这种使人衰弱的疾病的重要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Alzheimer's Disease 医学-神经科学

CiteScore

6.40

自引率

7.50%

发文量

1327

审稿时长

2 months

期刊介绍： The Journal of Alzheimer''s Disease (JAD) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer''s disease. The journal publishes research reports, reviews, short communications, hypotheses, ethics reviews, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer''s disease.