Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer’s disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance. First, we used gene ontology analysis of microglia from young and old mice to identify differential expression of cyclin-dependent kinase inhibitor 2A (p16ink4a), a cell cycle factor related to aging. We found that p16ink4a expression was increased in microglia near amyloid plaques in brain tissue from patients with AD and 5XFAD mice, a model of AD. In BV2 microglia, small interfering RNA (siRNA)-mediated p16ink4a downregulation transformed microglia with enhanced amyloid phagocytic capacity through regulated the cell cycle and increased cell proliferation. To regulate microglial phagocytosis by gene transduction, we used poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which predominantly target microglia, to deliver the siRNA and to control microglial reactivity. Nanoparticle-based delivery of p16ink4a siRNA reduced amyloid plaque formation and the number of aged microglia surrounding the plaque and reversed learning deterioration and spatial memory deficits. We propose that downregulation of p16ink4a in microglia is a promising strategy for the treatment of Alzheimer’s disease.

中文翻译：

---

通过负载 p16ink4a-siRNA 的纳米颗粒使衰老的小胶质细胞恢复活力可增加阿尔茨海默病动物模型中淀粉样蛋白 - β 的清除率

散发性阿尔茨海默病（AD）患者中淀粉样斑块的年龄依赖性积累与淀粉样蛋白清除率降低有关。较老的小胶质细胞吞噬淀粉样蛋白的能力降低，因此可以调节小胶质细胞对淀粉样斑块的吞噬作用以防止淀粉样蛋白积累。此外，考虑到老小胶质细胞中与衰老相关的细胞周期机制的破坏，我们假设调节它们的细胞周期可以使它们恢复活力并增强它们促进更有效的淀粉样蛋白清除的能力。首先，我们对年轻和年老小鼠的小胶质细胞进行基因本体分析，以确定细胞周期蛋白依赖性激酶抑制剂 2A (p16ink4a)（一种与衰老相关的细胞周期因子）的差异表达。我们发现 AD 患者和 AD 模型 5XFAD 小鼠脑组织中淀粉样斑块附近的小胶质细胞中 p16ink4a 表达增加。在 BV2 小胶质细胞中，小干扰 RNA (siRNA) 介导的 p16ink4a 下调通过调节细胞周期和增加细胞增殖来转化小胶质细胞，从而增强淀粉样蛋白吞噬能力。为了通过基因转导调节小胶质细胞的吞噬作用，我们使用了主要靶向小胶质细胞的聚（D,L-乳酸-乙醇酸）（PLGA）纳米颗粒来传递 siRNA 并控制小胶质细胞的反应性。基于纳米颗粒的 p16ink4a siRNA 递送减少了淀粉样斑块的形成和斑块周围老化小胶质细胞的数量，并逆转了学习退化和空间记忆缺陷。我们认为小胶质细胞中 p16ink4a 的下调是治疗阿尔茨海默病的一种有前途的策略。