Schubert P, Ogata T, Marchini C, Ferroni S
Department of Neuromorphology, Max Planck Institute of Neurobiology, Klopferspitz 18a, 82152, Martinsried, Germany.
Mech Ageing Dev. 2001 Dec;123(1):47-57. doi: 10.1016/s0047-6374(01)00343-8.
Reactive glial cell properties could contribute to pathomechanisms underlying Alzheimer's disease by favoring oxidative neuronal damage and beta-amyloid toxicity. A critical step is apparently reached when pathological glia activation is no longer restricted to microglia and includes astrocytes. By giving up their differentiated state, astrocytes may lose their physiological negative feed-back control on microglial NO production and even contribute to neurotoxic peroxynitrate formation. Another consequence is the impairment of the astrocyte-maintained extracellular ion homeostasis favoring excitotoxic damage. By the production of apolipoprotein-E, triggered by the microglial cytokine interleukine-1beta, reactive astrocytes could promote the transformation of beta-amyloid into the toxic form. A pharmacologically reinforced cAMP signaling in rat glial cell cultures depressed oxygen radical formation in microglia and their release of TNF-alpha and interleukine-1beta, feed-forward signals which mediate oxidative damage and secondary astrocyte activation. Cyclic AMP also favored differentiation and expression of a mature ion channel pattern in astrocytes improving their glutamate buffering. A deficient cholinergic signaling that increases the risk of pathological APP processing was compensated by an adenosine-mediated reinforcement of the second messenger calcium. A combination therapy with acetylcholine-esterase inhibitors together with adenosine raising pharmaca, therefore, may be used to treat cholinergic deficiency in Alzheimer's disease.
反应性胶质细胞特性可能通过促进氧化性神经元损伤和β-淀粉样蛋白毒性，对阿尔茨海默病的病理机制产生影响。当病理性胶质细胞激活不再局限于小胶质细胞，而是包括星形胶质细胞时，显然就达到了一个关键阶段。星形胶质细胞通过放弃其分化状态，可能会失去对小胶质细胞一氧化氮产生的生理性负反馈控制，甚至会促进神经毒性过氧亚硝酸盐的形成。另一个后果是星形胶质细胞维持的细胞外离子稳态受损，从而促进兴奋性毒性损伤。由小胶质细胞细胞因子白细胞介素-1β触发产生的载脂蛋白-E，反应性星形胶质细胞可能会促进β-淀粉样蛋白向毒性形式的转化。在大鼠胶质细胞培养物中，药理学增强的环磷酸腺苷（cAMP）信号传导可抑制小胶质细胞中的氧自由基形成及其肿瘤坏死因子-α和白细胞介素-1β的释放，这些前馈信号介导氧化损伤和继发性星形胶质细胞激活。环磷酸腺苷还有利于星形胶质细胞中成熟离子通道模式的分化和表达，从而改善其谷氨酸缓冲能力。增加病理性淀粉样前体蛋白（APP）加工风险的胆碱能信号传导缺陷，可通过腺苷介导的第二信使钙的增强来补偿。因此，乙酰胆碱酯酶抑制剂与腺苷增强药物的联合治疗可用于治疗阿尔茨海默病中的胆碱能缺乏。
