美国斯坦福大学医学院Jeffrey L. Goldberg研究组取得一项新突破。他们的最新研究揭示了神经保护性星形胶质细胞反应性的分子开关。该研究于2023年12月12日发表于国际学术期刊《自然》杂志。

研究人员发现受伤的白质星形胶质细胞分化为两种不同的C3阳性和C3阴性细胞反应群，以前被简化为神经毒性（A1）和神经保护性（A2）细胞群，它们又可进一步细分为以增殖和不同基因表达为特征的独特亚群。研究发现神经毒性星形胶质细胞与神经保护性星形胶质细胞之间的平衡，受可溶性腺苷酸环化酶（sAC）分区cAMP离散池的调节，并且增殖的神经保护性星形胶质细胞抑制了小胶质细胞的激活，和下游神经毒性星形胶质细胞的分化，从而促进视网膜神经节细胞（RGC）的存活。

最后，研究人员建立了一种新的、可治疗的病毒载体，该载体可特异性靶向视神经星形胶质细胞，并表明提高反应性星形胶质细胞核内或细胞质内的cAMP水平，可抑制有害小胶质细胞/巨噬细胞的活化，促进视神经损伤后RGC的存活。

因此，反应性星形胶质细胞中的可溶性腺苷酸环化酶和分区、细胞核和细胞质中的cAMP是神经保护性星形胶质细胞反应性的分子开关，可通过抑制小胶质细胞的活化和神经毒性星形胶质细胞的分化来达到治疗效果。这些数据扩展并定义了新的反应性星形胶质细胞亚型，向开发治疗青光眼和其他视神经病变的胶质治疗药物迈出了新的一步。

研究人员表示，调控星形胶质细胞神经毒性与神经保护性的内在机制，及其对中枢神经系统（CNS）变性和修复的影响仍鲜为人知。

附：英文原文

Title: A molecular switch for neuroprotective astrocyte reactivity

Author: Cameron, Evan G., Nahmou, Michael, Toth, Anna B., Heo, Lyong, Tanasa, Bogdan, Dalal, Roopa, Yan, Wenjun, Nallagatla, Pratima, Xia, Xin, Hay, Sarah, Knasel, Cara, Stiles, Travis L., Douglas, Christopher, Atkins, Melissa, Sun, Catalina, Ashouri, Masoumeh, Bian, Minjuan, Chang, Kun-Che, Russano, Kristina, Shah, Sahil, Woodworth, Mollie B., Galvao, Joana, Nair, Ramesh V., Kapiloff, Michael S., Goldberg, Jeffrey L.

Issue&Volume: 2023-12-12

Abstract: The intrinsic mechanisms that regulate neurotoxic versus neuroprotective astrocyte phenotypes and their effects on central nervous system (CNS) degeneration and repair remain poorly understood. Here, we show injured white matter astrocytes differentiate into two distinct C3-positive and C3-negative reactive populations, previously simplified as neurotoxic (A1) and neuroprotective (A2)1,2, which can be further subdivided into unique subpopulations defined by proliferation and differential gene expression signatures. We find the balance of neurotoxic versus neuroprotective astrocytes is regulated by discrete pools of compartmented cAMP derived from soluble adenylyl cyclase (sAC) and show proliferating neuroprotective astrocytes inhibit microglial activation and downstream neurotoxic astrocyte differentiation to promote retinal ganglion cell (RGC) survival. Finally, we report a new, therapeutically tractable viral vector to specifically target optic nerve head astrocytes and show elevating nuclear or depleting cytoplasmic cAMP in reactive astrocytes inhibits deleterious microglial/macrophage cell activation and promotes RGC survival after optic nerve injury. Thus, soluble adenylyl cyclase and compartmented, nuclear- and cytoplasmic-localized cAMP in reactive astrocytes act as a molecular switch for neuroprotective astrocyte reactivity that can be targeted to inhibit microglial activation and neurotoxic astrocyte differentiation to therapeutic effect. These data expand upon and define new reactive astrocyte subtypes and represent a novel step toward the development of gliotherapeutics for the treatment of glaucoma and other optic neuropathies.

DOI: 10.1038/s41586-023-06935-3

Source: https://www.nature.com/articles/s41586-023-06935-3