Melchiorri Daniela, Merlo Sara, Micallef Benjamin, Borg John-Joseph, Dráfi František
Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy.
Front Pharmacol. 2023 Jun 2;14:1196413. doi: 10.3389/fphar.2023.1196413. eCollection 2023.
Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer's disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of neurofibrillary tangles (NFTs) consisting of altered hyperphosphorylated tau protein. Both have been widely studied and pharmacologically targeted for many years, without significant therapeutic results. In 2022, positive data on two monoclonal antibodies targeting Aβ, donanemab and lecanemab, followed by the 2023 FDA accelerated approval of lecanemab and the publication of the final results of the phase III Clarity AD study, have strengthened the hypothesis of a causal role of Aβ in the pathogenesis of AD. However, the magnitude of the clinical effect elicited by the two drugs is limited, suggesting that additional pathological mechanisms may contribute to the disease. Cumulative studies have shown inflammation as one of the main contributors to the pathogenesis of AD, leading to the recognition of a specific role of neuroinflammation synergic with the Aβ and NFTs cascades. The present review provides an overview of the investigational drugs targeting neuroinflammation that are currently in clinical trials. Moreover, their mechanisms of action, their positioning in the pathological cascade of events that occur in the brain throughout AD disease and their potential benefit/limitation in the therapeutic strategy in AD are discussed and highlighted as well. In addition, the latest patent requests for inflammation-targeting therapeutics to be developed in AD will also be discussed.
尽管进行了广泛研究，但目前尚无能够预防、治愈或阻止阿尔茨海默病（AD）进展的疾病修饰治疗方案。AD是一种导致痴呆和死亡的毁灭性神经退行性疾病，其特征有两个病理标志，即细胞外淀粉样β蛋白（Aβ）沉积和由异常高磷酸化tau蛋白组成的神经原纤维缠结（NFTs）的神经元内沉积。多年来，这两者都得到了广泛研究并作为药物靶点，但没有取得显著的治疗效果。2022年，两种靶向Aβ的单克隆抗体多那奈单抗和乐卡奈单抗出现了阳性数据，随后2023年美国食品药品监督管理局（FDA）加速批准了乐卡奈单抗，并公布了III期Clarity AD研究的最终结果，这强化了Aβ在AD发病机制中起因果作用的假说。然而，这两种药物产生的临床效果程度有限，表明可能还有其他病理机制导致该疾病。累积研究表明炎症是AD发病机制的主要促成因素之一，这使得人们认识到神经炎症与Aβ和NFTs级联反应协同发挥的特定作用。本综述概述了目前正在进行临床试验的靶向神经炎症的研究药物。此外，还讨论并强调了它们的作用机制、在AD整个病程中大脑发生的病理事件级联反应中的定位以及它们在AD治疗策略中的潜在益处/局限性。此外，还将讨论AD中针对炎症的治疗药物的最新专利申请。
