Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, School of Health Sciences, Central University of Punjab, Bathinda-151401, Punjab, India.
Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, School of Health Sciences, Central University of Punjab, Bathinda-151401, Punjab, India.
Int Immunopharmacol. 2024 Nov 15;141:112940. doi: 10.1016/j.intimp.2024.112940. Epub 2024 Aug 17.
Alzheimer's disease (AD) is one of the most debilitating age-related disorders that affect people globally. It impacts social and cognitive behavior of the individual and is characterized by phosphorylated tau and Aβ accumulation. Astrocytesmaintain a quiescent, anti-inflammatory state on anatomical level, expressing few cytokines and exhibit phagocytic activity to remove misfolded proteins. But in AD, in response to specific stimuli, astrocytes overstimulate their phagocytic character with overexpressing cytokine gene modules. Upon interaction with generated Aβ and neurofibrillary tangle, astrocytes that are continuously activated release a large number of inflammatory cytokines. This cytokine storm leads to neuroinflammation which is also one of the recognizable features of AD. Astrogliosis eventually promotes cholinergic dysfunction, calcium imbalance, oxidative stress and excitotoxicity. Furthermore, C5aR1, Lcn2/, BDNF/TrkB and PPARα/TFEB signaling dysregulation has a major impact on the disease progression. This review clarifies numerous ways that lead to astrogliosis, which is stimulated by a variety of processes that exacerbate AD pathology and make it a suitable target for AD treatment. Drugs under clinical and preclinical investigations that target several pathways managing astrogliosis and are efficacious in ameliorating the pathology of the disease are also included in this study. D-ALA2GIP, TRAM-34, Genistein, L-serine, MW150 and XPro1595 are examples of few drugs targeting astrogliosis. Therefore, this study may aid in the development of a potent therapeutic agent for ameliorating astrogliosis mediated AD progression.
阿尔茨海默病（AD）是全球范围内最具破坏性的与年龄相关的疾病之一，影响着人们的社交和认知行为。它的特征是磷酸化 tau 和 Aβ 的积累。星形胶质细胞在解剖学水平上保持静止、抗炎状态，表达少量细胞因子，并具有吞噬功能以清除错误折叠的蛋白质。但在 AD 中，星形胶质细胞对特定刺激过度反应，过度表达细胞因子基因模块，过度刺激其吞噬特性。当与产生的 Aβ 和神经原纤维缠结相互作用时，持续激活的星形胶质细胞会释放大量炎症细胞因子。这种细胞因子风暴导致神经炎症，这也是 AD 的一个可识别特征。星形胶质细胞增生最终导致胆碱能功能障碍、钙失衡、氧化应激和兴奋毒性。此外，C5aR1、Lcn2/、BDNF/TrkB 和 PPARα/TFEB 信号转导失调对疾病进展有重大影响。本综述阐明了导致星形胶质细胞增生的多种途径，这些途径受到各种加剧 AD 病理的过程的刺激，使其成为 AD 治疗的合适靶点。本研究还包括了正在临床和临床前研究中针对几种管理星形胶质细胞增生的途径的药物，这些药物在改善疾病的病理方面是有效的。D-ALA2GIP、TRAM-34、染料木素、L-丝氨酸、MW150 和 XPro1595 是几种靶向星形胶质细胞增生的药物的例子。因此，本研究可能有助于开发一种有效的治疗剂，以改善星形胶质细胞增生介导的 AD 进展。
