López-Hernández Rubén, de la Torre-Álamo María Magdalena, García-Bueno Belén, Baroja-Mazo Alberto, Fenoy Francisco Jose, Cuevas Santiago
Molecular Inflammation Group, Pathophysiology of the Inflammation and Oxidative Stress Lab, Biomedical Research Institute of Murcia (IMIB), University Clinical Hospital Virgen de la Arrixaca, 30120 Murcia, Spain.
Molecular Inflammation Group, Digestive and Endocrine Surgery and Transplantation of Abdominal Organs, Biomedical Research Institute of Murcia (IMIB), University Clinical Hospital Virgen de la Arrixaca, 30120 Murcia, Spain.
Antioxidants (Basel). 2025 Jan 21;14(2):121. doi: 10.3390/antiox14020121.
Current knowledge about Alzheimer's disease highlights the accumulation of β-amyloid plaques (Aβ1-42) and neurofibrillary tangles composed of hyperphosphorylated Tau, which lead to the loss of neuronal connections. Microglial activation and the release of inflammatory mediators play a significant role in the progression of Alzheimer's pathology. Recent advances have identified the involvement of inflammasomes, particularly NOD-like receptor NLR family pyrin domain containing 3 (NLRP3), whose activation promotes the release of proinflammatory cytokines and triggers pyroptosis, exacerbating neuroinflammation. Aggregates of Aβ1-42 and hyperphosphorylated Tau have been shown to activate these inflammasomes, while the apoptosis-associated speck-like protein (ASC) components form aggregates that further accelerate Aβ aggregation. Defects in the autophagic clearance of inflammasomes have also been implicated in Alzheimer's disease, contributing to sustained inflammation. This review explores strategies to counteract inflammation in Alzheimer's, emphasizing the degradation of ASC specks and the inhibition of NLRP3 inflammasome activation. Notably, the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor emerges as a promising therapeutic target due to its dual role in mitigating oxidative stress and directly inhibiting NLRP3 inflammasome formation. By reducing inflammasome-driven inflammation, Nrf2 offers significant potential for addressing the neuroinflammatory aspects of Alzheimer's disease.
目前关于阿尔茨海默病的知识强调了β-淀粉样蛋白斑块（Aβ1-42）的积累以及由过度磷酸化的 Tau 组成的神经纤维缠结，这些会导致神经元连接的丧失。小胶质细胞激活和炎症介质的释放在阿尔茨海默病病理进展中起重要作用。最近的进展已确定炎性小体的参与，特别是含核苷酸结合寡聚化结构域样受体 NLR 家族含 pyrin 结构域 3（NLRP3），其激活促进促炎细胞因子的释放并引发细胞焦亡，加剧神经炎症。已证明 Aβ1-42 聚集体和过度磷酸化的 Tau 会激活这些炎性小体，而凋亡相关斑点样蛋白（ASC）成分形成聚集体，进一步加速 Aβ 聚集。炎性小体自噬清除缺陷也与阿尔茨海默病有关，导致持续炎症。本综述探讨了对抗阿尔茨海默病炎症的策略，强调 ASC 斑点的降解和 NLRP3 炎性小体激活的抑制。值得注意的是，核因子红细胞 2 相关因子 2（Nrf2）转录因子因其在减轻氧化应激和直接抑制 NLRP3 炎性小体形成方面的双重作用而成为一个有前景的治疗靶点。通过减少炎性小体驱动的炎症，Nrf2 在解决阿尔茨海默病的神经炎症方面具有巨大潜力。
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