Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity
Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity
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DOI：
10.1007/s12031-020-01747-w
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发表时间：
2021-01-08
影响因子：
3.1
通讯作者：
Adeniyi, Philip Adeyemi
中科院分区：
文献类型：
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作者：
Olajide, Olayemi Joseph;Gbadamosi, Ismail Tayo;Adeniyi, Philip Adeyemi
阿尔茨海默病（AD）病理学的标志包括老年斑积聚和神经元缠结，这被认为是突触失效的基础。然而，最近的证据支持，AD中的突触失败可能是由增强的N-甲基-D-天冬氨酸（NMDA）活性通过可溶性淀粉样蛋白-β（A β）积累和增加的谷氨酸激动剂之间的相互关系引起的。虽然先前的研究已经表明AD期间A β介导的谷氨酸能系统的改变，但尚未探索兴奋性毒性谷氨酸诱导的变化的潜在病因。在这里，我们研究了急性立体定位齿状回（DG）谷氨酸注射对行为和特定的蛋白质和神经化学物质的分子表达调节海马功能。使用NMDA受体拮抗剂美金刚测试谷氨酸介导的作用对NMDA受体（NMDAR）超活化的依赖性。对Wistar大鼠（12周龄）的DG进行双侧微量注射谷氨酸（500 mM），每天腹腔注射或不注射（i. p.）美金刚注射（20 mg/kg）14天，而对照接受海马内/腹膜内PBS或腹膜内美金刚。在旷场和Y-迷宫中的行为表征显示，谷氨酸引起的焦虑反应和干扰的空间记忆被美金刚抑制。在谷氨酸处理的大鼠，NO的表达增加伴随着显着减少谷胱甘肽-S-转移酶和谷胱甘肽过氧化物酶的配置文件。同样，谷氨酸介导的乙酰胆碱酯酶表达的增加证实了突触素和PSD-95的下调，加上反应性星形胶质细胞增生（GFAP）的启动。虽然神经丝免疫定位/免疫表达未受干扰，但我们发现谷氨酸介导的神经原性标志物Ki 67和PCNA免疫表达减少，NR 2B蛋白表达减少，而mGluR 1保持不变。此外，在谷氨酸输注大鼠中，凋亡调节蛋白p53和Bax的表达增加，证实DG中颗粒神经元的溶色变性。有趣的是，在这项研究中，美金刚消除了大多数与谷氨酸兴奋性毒性相关的退行性变化。综上所述，我们的研究结果将DG中的急性谷氨酸平衡障碍与AD相关行为障碍和分子神经退行性变的发展联系起来。
The hallmarks of Alzheimer's disease (AD) pathology include senile plaques accumulation and neurofibrillary tangles, which is thought to underlie synaptic failure. Recent evidence however supports that synaptic failure in AD may instead be instigated by enhanced N-methyl-D-aspartate (NMDA) activity, via a reciprocal relationship between soluble amyloid-beta (A beta) accumulation and increased glutamate agonist. While previous studies have shown A beta-mediated alterations to the glutamatergic system during AD, the underlying etiology of excitotoxic glutamate-induced changes has not been explored. Here, we investigated the acute effects of stereotaxic dentate gyrus (DG) glutamate injection on behavior and molecular expression of specific proteins and neurochemicals modulating hippocampal functions. Dependence of glutamate-mediated effects on NMDA receptor (NMDAR) hyperactivation was tested using NMDARs antagonist memantine. DG of Wistar rats (12-weeks-old) were bilaterally microinjected with glutamate (500 mM) with or without daily intraperitoneal (i.p.) memantine injection (20 mg/kg) for 14 days, while controls received either intrahippocampal/i.p. PBS or i.p. memantine. Behavioral characterization in open field and Y-maze revealed that glutamate evoked anxiogenic responses and perturbed spatial memory were inhibited by memantine. In glutamate-treated rats, increased NO expression was accompanied by marked reduction in profiles of glutathione-s-transferase and glutathione peroxidase. Similarly, glutamate-mediated increase in acetylcholinesterase expression corroborated downregulation of synaptophysin and PSD-95, coupled with initiation of reactive astrogliosis (GFAP). While neurofilament immunolocalization/immunoexpression was unperturbed, we found glutamate-mediated reduction in neurogenic markers Ki67 and PCNA immunoexpression, with a decrease in NR2B protein expression, whereas mGluR1 remains unchanged. In addition, increased expression of apoptotic regulatory proteins p53 and Bax was seen in glutamate infused rats, corroborating chromatolytic degeneration of granule neurons in the DG. Interestingly, memantine abrogated most of the degenerative changes associated with glutamate excitotoxicity in this study. Taken together, our findings causally link acute glutamate dyshomeostasis in the DG with development of AD-related behavioral impairment and molecular neurodegeneration.