Brain dysfunction induced by tyrosine nitrosylation of synaptic protein

本研究从诱导型一氧化氮合酶（iNOS）、氧化应激、细胞内信号转导和神经递质受体等方面探讨了β淀粉样蛋白（Aβ）诱导脑功能障碍的机制。大鼠侧脑室持续灌注Aβ可引起海马iNOS表达、NO过量产生和突触体蛋白酪氨酸硝化。iNOS抑制剂和过氧亚硝酸盐清除剂可预防Aβ诱导的记忆障碍和尼古丁诱发的海马中乙酰胆碱（ACh）释放。Aβ输注还导致抗氧化物质（如谷胱甘肽）显著减少。这些发现表明氧化应激在Aβ诱导的脑功能障碍中的作用。此外，慢性Aβ灌注降低海马蛋白激酶C的活性，并消除佛波醇二丁酸酯诱导的移位。关于Aβ诱导的神经递质受体功能改变，我们重点关注α7烟碱型ACh受体（nAChR）和N-甲基-D-天冬氨酸受体（NMDAR）的作用。应用实时光学记录技术，观察了Aβ注射大鼠海马脑片Schaffer侧支-CA 1突触的基础突触传递和长时程增强（LTP）的损伤。慢性Aβ输注减弱了对α7 nAChR激动剂的反应性，而选择性拮抗剂阻断受体导致对照动物海马LTP的缺陷。用α7 nAChR激动剂预处理Aβ灌注的大鼠脑片可逆转LTP的缺陷。提示α7 nAChR功能障碍在Aβ诱导的海马LTP损伤中起重要作用。最后，我们发现，美金刚胺，一种低亲和力的NMDAR拮抗剂，防止Aβ处理的大鼠的短期记忆障碍的发展。提示α7 nAChR和NMDAR可能是阿尔茨海默病药物开发的重要靶点。

We have investigated the mechanisms of brain dysfunction induced by amyloid β(Aβ) in relation to inducible nitric oxide(NO) synthase (iNOS), oxidative stress, intracellular signaling and neurotransmitter receptors. Continuous infusion of Aβ into the cerebroventricle in rats resulted in the expression of iNOS, overproduction of NO and tyrosine nitration of synaptophysin in the hippocampus. The iNOS inhibitors and peroxynitrite scavengers prevented the Aβ-induced impairment of memory and nicotine-evoked acetylcholine(ACh) release in the hippocampus. Aβ infusion also resulted in a significant reduction of antioxidant substances such as glutathione. These findings suggest a role for oxidative stress in Aβ-induced brain dysfunction. Furthermore, chronic infusion of Aβ decreased the activity of protein kinase C in the hippocampus and abolished the translocation induced by phorbol-dibutyrate. Regarding the functional alterations of neurotransmitter receptors induced by Aβ, we focused on the role of α7 nicotinic ACh receptors(nAChR) and N-methyl-D-aspartate receptors(NMDAR). By using a real-time optical recording technique, we found an impairment of the basal synaptic transmission and long-term potentiation(LTP) at the Schaffer collateral-CA1 synapse in the hippocampal slices from Aβ-infused rats. Chronic Aβ infusion attenuated the responsibility to the α7 nAChR agonist while the blockade of the receptors with selective antagonists led to the deficit in the hippocampal LTP in control animals. Pretreatment with α7 nAChR agonist of the slices from Aβ-infused rats reversed the deficit in LTP. These results suggest that dysfunction of α7 nAChR plays a crucial role in Aβ-induced impairment of LTP in the hippocampus. Lastly, we found that memantine, a low affinity NMDAR antagonist, prevented the development of short-term memory deficit in Aβ-treated rats. It is suggested that both α7 nAChR and NMDAR could be important targets for drug development in Alzheimer's disease.