Chamorro Laia Berridi, Zulli Barbara, Barone Eugenio
Faculty of Science, University of Amsterdam, Amsterdam, the Netherlands.
Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Rome, Italy.
J Neural Transm (Vienna). 2025 May 31. doi: 10.1007/s00702-025-02956-6.
The growing prevalence of age-related neurodegenerative diseases is a consequence of population aging and demands urgent treatment strategies. This literature review aims to provide a comprehensive overview of the contribution of oxidative stress and insulin resistance in neurodegenerative diseases, specifically Alzheimer's disease (AD). In addition, current therapeutic approaches to treat oxidative stress and insulin resistance in this age-related neurodegenerative disease will be discussed. AD is the most prevalent form of neurodegenerative disease and is marked at early stages by oxidative stress and insulin resistance. Results indicate that insulin resistance may be central in generating oxidative stress and exacerbating AD hallmarks. In turn, insulin resistance can be influenced by other factors, including amyloid beta (Aβ), impaired biliverdin-reductase A (BVR-A) activity, and the gut microbiota. Defective insulin signaling in the brain comes with consequences ranging from declined cognitive functions, impaired autophagy, mitochondrial dysfunction, hyperphosphorylation of Tau, and increased Aβ production. Multiple therapeutic approaches that target oxidative stress or brain insulin resistance, such as antioxidant supplementation and anti-diabetic drugs, have mostly been inconclusive, except for intranasal insulin. Positive results have been obtained in clinical trials using nasal delivery devices to administer insulin; however, results are inconsistent across studies likely due to inconsistencies in the delivery method. Future investigations should focus on investigating the molecular link between oxidative stress, insulin resistance, and AD to address current knowledge gaps. Moreover, more focus should be given to optimizing the reliability and efficacy of nasal delivery devices before considering such an approach viable to treat neurodegenerative diseases.
与年龄相关的神经退行性疾病患病率不断上升是人口老龄化的结果，迫切需要治疗策略。这篇文献综述旨在全面概述氧化应激和胰岛素抵抗在神经退行性疾病，特别是阿尔茨海默病（AD）中的作用。此外，还将讨论目前针对这种与年龄相关的神经退行性疾病中氧化应激和胰岛素抵抗的治疗方法。AD是最常见的神经退行性疾病形式，在早期以氧化应激和胰岛素抵抗为特征。结果表明，胰岛素抵抗可能是产生氧化应激和加剧AD特征的核心因素。反过来，胰岛素抵抗可能会受到其他因素的影响，包括β-淀粉样蛋白（Aβ）、胆红素还原酶A（BVR-A）活性受损和肠道微生物群。大脑中胰岛素信号传导缺陷会导致认知功能下降、自噬受损、线粒体功能障碍、Tau蛋白过度磷酸化以及Aβ生成增加等后果。除了鼻内胰岛素外，多种针对氧化应激或大脑胰岛素抵抗的治疗方法，如补充抗氧化剂和抗糖尿病药物，大多尚无定论。使用鼻内给药装置给药胰岛素的临床试验已取得了积极结果；然而，由于给药方法不一致，各研究结果并不一致。未来的研究应专注于研究氧化应激、胰岛素抵抗和AD之间的分子联系，以填补当前的知识空白。此外，在考虑将这种方法作为治疗神经退行性疾病的可行方法之前，应更加注重优化鼻内给药装置的可靠性和有效性。
