Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700 032, India.
Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700 032, India.
Neurochem Int. 2021 May;145:104956. doi: 10.1016/j.neuint.2021.104956. Epub 2021 Jan 24.
Astrocytes respond to any pathological condition in the central nervous system (CNS) including Alzheimer's disease (AD), and this response is called astrocyte reactivity. Astrocyte reaction to a CNS insult is a highly heterogeneous phenomenon in which the astrocytes undergo a set of morphological, molecular and functional changes with a characteristic secretome profile. Such astrocytes are termed as 'reactive astrocytes'. Controversies regarding the reactive astrocytes abound. Recently, a continuum of reactive astrocyte profiles with distinct transcriptional states has been identified. Among them, disease-associated astrocytes (DAA) were uniquely present in AD mice and expressed a signature set of genes implicated in complement cascade, endocytosis and aging. Earlier, two stimulus-specific reactive astrocyte subtypes with their unique transcriptomic signatures were identified using mouse models of neuroinflammation and ischemia and termed as A1 astrocytes (detrimental) and A2 astrocytes (beneficial) respectively. Interestingly, although most of the A1 signature genes were also detected in DAA, as opposed to A2 astrocyte signatures, some of the A1 specific genes were expressed in other astrocyte subtypes, indicating that these nomenclature-based signatures are not very specific. In this review, we elaborate the disparate functions and cytokine profiles of reactive astrocyte subtypes in AD and tried to distinguish them by designating neurotoxic astrocytes as A1-like and neuroprotective ones as A2-like without directly referring to the A1/A2 original nomenclature. We have also focused on the dual nature from a functional perspective of some cytokines depending on AD-stage, highlighting a number of them as major candidates in AD therapy. Therefore, we suggest that promoting subtype-specific beneficial roles, inhibiting subtype-specific detrimental roles or targeting subtype-specific cytokines constitute a novel therapeutic approach to AD treatment.
星形胶质细胞对中枢神经系统（CNS）中的任何病理状况都有反应，包括阿尔茨海默病（AD），这种反应称为星形胶质细胞反应性。星形胶质细胞对 CNS 损伤的反应是一种高度异质的现象，其中星形胶质细胞经历一组形态、分子和功能变化，并具有特征性的分泌组谱。这种星形胶质细胞被称为“反应性星形胶质细胞”。关于反应性星形胶质细胞存在很多争议。最近，已经确定了具有不同转录状态的反应性星形胶质细胞连续谱。其中，疾病相关星形胶质细胞（DAA）在 AD 小鼠中特异地存在，并表达了一组与补体级联、内吞作用和衰老相关的特征基因。早些时候，使用神经炎症和缺血的小鼠模型，鉴定出两种具有独特转录组特征的刺激特异性反应性星形胶质细胞亚型，并分别命名为 A1 星形胶质细胞（有害）和 A2 星形胶质细胞（有益）。有趣的是，尽管大多数 A1 特征基因也在 DAA 中检测到，而不是 A2 星形胶质细胞特征基因，但一些 A1 特异性基因在其他星形胶质细胞亚型中表达，这表明这些基于命名的特征基因不是非常特异的。在这篇综述中，我们详细阐述了 AD 中反应性星形胶质细胞亚型的不同功能和细胞因子谱，并试图通过将神经毒性星形胶质细胞指定为 A1 样，将神经保护星形胶质细胞指定为 A2 样，而不直接引用 A1/A2 原始命名来区分它们。我们还从功能角度关注了一些细胞因子的双重性质，根据 AD 阶段强调了其中的一些作为 AD 治疗的主要候选物。因此，我们建议促进特定亚型的有益作用，抑制特定亚型的有害作用，或针对特定亚型的细胞因子，构成 AD 治疗的一种新的治疗方法。
