Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA, USA.
Department of Neurology & Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
J Cereb Blood Flow Metab. 2019 Nov;39(11):2157-2171. doi: 10.1177/0271678X18783653. Epub 2018 Jun 12.
Cerebral ischemia has a harmful effect on the synapse associated with neurological impairment. The "tripartite synapse" is assembled by the pre- and postsynaptic terminals, embraced by astrocytic elongations known as peripheral astrocytic processes (PAPs). Ischemic stroke induces the detachment of PAPs from the synapse, leading to synaptic dysfunction and neuronal death. Ezrin is a membrane-associated protein, required for the formation of PAPs, that links the cell surface to the actin cytoskeleton. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) promotes neurite growth during development. In the adult brain, neurons release uPA and astrocytes recruit uPAR to the plasma membrane during the recovery phase from an ischemic stroke, and uPA/uPAR binding promotes functional improvement following an ischemic injury. We found that uPA induces the synthesis of ezrin in astrocytes, with the subsequent formation of PAPs that enter in direct contact with the synapse. Furthermore, either the release of neuronal uPA or intravenous treatment with recombinant uPA (ruPA) induces the formation of PAPs in the ischemic brain, and the interaction of these PAPs with the pre- and postsynaptic terminals protects the integrity of the "tripartite synapse" from the harmful effects of the ischemic injury.
脑缺血对与神经功能损伤相关的突触有有害影响。“三分突触”由前突触和后突触末端组装，被称为周围星形胶质突起（PAPs）的星形胶质细胞延伸所包围。缺血性中风会导致 PAPs 从突触上脱离，从而导致突触功能障碍和神经元死亡。埃兹蛋白是一种膜相关蛋白，是 PAPs 形成所必需的，它将细胞膜与肌动蛋白细胞骨架连接起来。尿激酶型纤溶酶原激活物（uPA）是一种丝氨酸蛋白酶，在与受体（uPAR）结合后，在发育过程中促进神经突生长。在成年大脑中，神经元在缺血性中风后的恢复阶段释放 uPA，星形胶质细胞招募 uPAR 到质膜上，uPA/uPAR 结合促进缺血性损伤后的功能改善。我们发现 uPA 诱导星形胶质细胞合成埃兹蛋白，随后形成与突触直接接触的 PAPs。此外，神经元释放 uPA 或静脉内给予重组 uPA（ruPA）均可诱导缺血性脑内形成 PAPs，这些 PAPs 与前突触和后突触末端相互作用，保护“三分突触”的完整性免受缺血性损伤的有害影响。
