Brain dysfunction induced by tyrosine nitrosylation of synaptic protein

我们研究了β淀粉样蛋白（Aβ）诱导的脑功能障碍的机制，涉及诱导型一氧化氮（NO）合成酶（iNOS）、氧化应激、细胞内信号传导和神经递质受体。大鼠脑室持续输注Aβ，导致海马内iNOS的表达、NO的过量产生和突触素的酪氨酸硝化。iNOS抑制剂和过氧亚硝酸盐清除剂可阻止a β诱导的记忆损伤和尼古丁诱发的海马乙酰胆碱（ACh）释放。a β输注也导致抗氧化物质如谷胱甘肽的显著减少。这些发现提示了氧化应激在a β诱导的脑功能障碍中的作用。此外，长期输注Aβ可降低海马蛋白激酶C的活性，消除二丁酸磷诱导的易位。关于α β诱导的神经递质受体的功能改变，我们重点研究了α - 7烟碱ACh受体（nAChR）和n -甲基- d -天冬氨酸受体（NMDAR）的作用。通过实时光学记录技术，我们发现a β注入大鼠海马切片中Schaffer侧侧- ca1突触的基础突触传递和长期增强（LTP）功能受损。慢性Aβ输注减轻了α7 nAChR激动剂的作用，而选择性拮抗剂阻断受体导致对照动物海马LTP的缺陷。α - 7 nAChR激动剂预处理a β注入大鼠的切片，可逆转LTP的缺陷。这些结果表明α7 nAChR功能障碍在a β诱导的海马LTP损伤中起重要作用。最后，我们发现美金刚，一种低亲和力的NMDAR拮抗剂，阻止了a β处理大鼠短期记忆缺陷的发展。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.