Kumari Sneha, Dhapola Rishika, Sharma Prajjwal, Singh Sunil K, Reddy Dibbanti HariKrishna
Department of Pharmacology, School of Health Sciences, Central University of Punjab, Ghudda, Bathinda-151401, Punjab, India.
Department of Zoology, School of Biological Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India.
Ageing Res Rev. 2023 Oct 28:102098. doi: 10.1016/j.arr.2023.102098.
Alzheimer's Disease (AD) is one of the most devastating age-related disorder causing significant social and economic burden worldwide. It affects the cognitive and social behavior of individuals and characterized by accumulation of Aβ, phosphorylated tau and cytokines formation. The synthesis and release of cytokines are regulated by specific groups of immune and non-immune cells in response to microglia or astrocyte activation through multiple pathways. Physiologically, microglia assert an anti-inflammatory, quiescent state with minimal cytokine expression and little phagocytic activity in motion to carry out their housekeeping role to eliminate pathogens, aggregated Aβ and tau protein. However, they develop a phagocytic nature and overexpress cytokine gene modules in response to certain stimuli in AD. Microglia and astrocytes upon chronic activation release an enormous amount of inflammatory cytokines due to interaction with formed Aβ and neurofibrillary tangle. Gut microbiota dysbiosis also stimulates the release of inflammatory cytokines contributing to AD pathogenesis. In addition, the dysregulation of few signaling pathways significantly influences the development of disease, and the pace of advancement also rises with age. This review sheds light on multiple pathways results into neuroinflammation triggered by activated cytokines worsening AD pathology and making it an appropriate target for AD treatment. This review also included drugs targeting different neuroinflammation pathways under clinical and preclinical studies that are found to be effective in attenuating the disease pathology.
阿尔茨海默病（AD）是最具破坏性的与年龄相关的疾病之一，在全球范围内造成了巨大的社会和经济负担。它影响个体的认知和社会行为，其特征是β淀粉样蛋白（Aβ）积累、tau蛋白磷酸化以及细胞因子形成。细胞因子的合成和释放由特定的免疫细胞和非免疫细胞群调节，这些细胞通过多种途径对小胶质细胞或星形胶质细胞的激活作出反应。在生理状态下，小胶质细胞处于抗炎的静止状态，细胞因子表达极少，吞噬活性也很低，以执行其清除病原体、聚集的Aβ和tau蛋白的清理功能。然而，在AD中，它们会因某些刺激而产生吞噬特性并过度表达细胞因子基因模块。长期激活后，小胶质细胞和星形胶质细胞由于与形成的Aβ和神经原纤维缠结相互作用而释放大量炎性细胞因子。肠道微生物群失调也会刺激炎性细胞因子的释放，促进AD的发病机制。此外，少数信号通路的失调显著影响疾病的发展，且疾病进展速度也随年龄增长而加快。本综述揭示了多种导致神经炎症的途径，这些途径由激活的细胞因子引发，会加剧AD病理变化，使其成为AD治疗的合适靶点。本综述还纳入了针对不同神经炎症途径的药物，这些药物在临床和临床前研究中被发现可有效减轻疾病病理。
