Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
Institute of Applied Physics "Nello Carrara", National Research Council (IFAC-CNR), Via Madonna del Piano 10, 50019 Florence, Italy.
Int J Mol Sci. 2023 Sep 5;24(18):13668. doi: 10.3390/ijms241813668.
Phenomics, the complexity of microglia phenotypes and their related functions compels the continuous study of microglia in disease animal models to find druggable targets for neurodegenerative disorders. Activation of microglia was long considered detrimental for neuron survival, but more recently it has become apparent that the real scenario of microglia morphofunctional diversity is far more complex. In this review, we discuss the recent literature on the alterations in microglia phenomics in the hippocampus of animal models of normal brain aging, acute neuroinflammation, ischemia, and neurodegenerative disorders, such as AD. Microglia undergo phenomic changes consisting of transcriptional, functional, and morphological changes that transform them into cells with different properties and functions. The classical subdivision of microglia into M1 and M2, two different, all-or-nothing states is too simplistic, and does not correspond to the variety of phenotypes recently discovered in the brain. We will discuss the phenomic modifications of microglia focusing not only on the differences in microglia reactivity in the diverse models of neurodegenerative disorders, but also among different areas of the brain. For instance, in contiguous and highly interconnected regions of the rat hippocampus, microglia show a differential, finely regulated, and region-specific reactivity, demonstrating that microglia responses are not uniform, but vary significantly from area to area in response to insults. It is of great interest to verify whether the differences in microglia reactivity may explain the differential susceptibility of different brain areas to insults, and particularly the higher sensitivity of CA1 pyramidal neurons to inflammatory stimuli. Understanding the spatiotemporal heterogeneity of microglia phenomics in health and disease is of paramount importance to find new druggable targets for the development of novel microglia-targeted therapies in different CNS disorders. This will allow interventions in three different ways: (i) by suppressing the pro-inflammatory properties of microglia to limit the deleterious effect of their activation; (ii) by modulating microglia phenotypic change to favor anti-inflammatory properties; (iii) by influencing microglia priming early in the disease process.
表型组学，即小胶质细胞表型及其相关功能的复杂性，迫使人们不断在疾病动物模型中研究小胶质细胞，以寻找神经退行性疾病的药物靶点。长期以来，小胶质细胞的激活被认为对神经元的存活有害，但最近人们显然意识到，小胶质细胞形态功能多样性的真实情况要复杂得多。在这篇综述中，我们讨论了关于正常大脑衰老、急性神经炎症、缺血和神经退行性疾病（如 AD）动物模型中海马中小胶质细胞表型改变的最新文献。小胶质细胞发生表型改变，包括转录、功能和形态改变，使它们转化为具有不同特性和功能的细胞。将小胶质细胞经典地分为 M1 和 M2 两种不同的、全有或全无的状态过于简单化，与最近在大脑中发现的多种表型并不相符。我们将讨论小胶质细胞的表型修饰，不仅关注不同神经退行性疾病模型中小胶质细胞反应的差异，还关注大脑不同区域之间的差异。例如，在大鼠海马的连续且高度互联区域，小胶质细胞表现出不同的、精细调节的、区域特异性的反应性，表明小胶质细胞的反应不是均匀的，而是根据区域的不同，对损伤的反应有很大差异。验证小胶质细胞反应的差异是否可以解释不同大脑区域对损伤的不同敏感性，特别是 CA1 锥体神经元对炎症刺激的更高敏感性，是非常有趣的。了解健康和疾病中小胶质细胞表型组学的时空异质性对于寻找新的药物靶点，以开发不同中枢神经系统疾病的新型小胶质细胞靶向治疗方法至关重要。这将允许通过三种不同的方式进行干预：（i）通过抑制小胶质细胞的促炎特性来限制其激活的有害影响；（ii）通过调节小胶质细胞表型改变来促进抗炎特性；（iii）通过在疾病早期影响小胶质细胞的启动。
