在中内嗅皮层表达异常Tau蛋白引起神经元活性下降及认知障碍

发布时间：2018-07-05 19:48

  本文选题：老年痴呆症 + 神经元活性　； 参考：《华中科技大学》2014年博士论文

【摘要】：阿尔茨海默氏病(AD)至关重要的特征性病理改变之一是异常改变的微管相关Tau蛋白选择性在不同类型的神经细胞内形成神经纤维缠结。根据Braak分期,内嗅皮层是最早出现异常Tau蛋白的皮层,并且一些影像学结果也显示了神经元活性的下降与Braak分期一致。为了解异常Tau蛋白对神经元活性的影响,我们在小鼠的中内嗅皮层(Media entorhinal cortex, MEC)表达P301LTau或过表达人Tau40蛋白来模拟早期AD病人。结果发现,在MEC表达P301LTau蛋白一个月后可以引起小鼠认知障碍,而在MEC过表达Tau40一个月不会引起小鼠认知障碍。MEC表达P301LTau蛋白一个月后可引起Tau蛋白过度磷酸化、突触可塑性下降以及神经元活性的下降；MEC过表达Tau40一个月后可明显抑制神经元活性。在MEC过表达Tau40三个月及六个月可引起依赖嗅觉的记忆下降,但空间记忆没有受损。在MEC过表达Tau40三个月即出现Tau蛋白的传播。 近来研究结果表明痴呆和低血压之间有相关性。低血压是如何增高老年痴呆(AD)风险的机制尚不清楚。我们对成年Sprague-Dawley (SD)大鼠给予过量的血管紧张素Ⅱ一型受体(AT1)抑制剂氯沙坦一个月后能够引起慢性、持续性低血压,并伴随有氧化应激反应。而且,我们发现氯沙坦导致非激活形式的PP2A水平上升,Tau蛋白的Ser199和Ser396位点出现过度磷酸化。给予氯沙坦的大鼠表现出记忆缺陷和大脑皮层树突棘密度的下降。这些结果表明过量氯沙坦引起的低血压可能通过氧化应激导致Tau蛋白过度磷酸化和树突棘丢失,从而增加了AD样病理改变和行为学异常的风险。 阿尔兹海默病(AD)是最常见的神经退行性疾病,绝大多数AD病人都是晚发散发形式。所以,研究环境因素是如何影响和促进AD的发病具有重要意义。目前,社会隔离(social isolation, SI)这种环境因素对野生型小鼠认知的影响尚不清楚。SI是否会引起肾上腺素能信号通路改变,SI与AD的发病机制的关系也不清楚。为了研究上述问题,我们将刚断奶的3周龄小鼠进行SI喂养6周,结果发现SI小鼠依赖杏仁核的条件恐惧记忆下降并伴随焦虑情绪出现,同时依赖海马的空间学习能力下降。SI小鼠肾上腺素能信号通路激活,淀粉样前体蛋白(APP)淀粉样剪切途径被激活并导致Aβ40的表达增高。SI的突触可塑性受到了明显的抑制。用βR抑制剂普萘洛尔喂养SI小鼠可以改善SI小鼠的认知障碍。
[Abstract]:One of the most important characteristic pathological changes in Alzheimer's disease (AD) is the selective formation of neurofibrillary tangles in different types of nerve cells by abnormal changes of microtubule-associated Tau protein. According to Braak stage, the endoolfactory cortex is the earliest cortex with abnormal Tau protein, and some imaging results show that the decrease of neuron activity is consistent with Braak stage. In order to understand the effect of abnormal entorhinal on neuronal activity, we expressed P301 LTau or over-expressed human Tau40 protein in mouse entorhinal cortexes to mimic early AD patients. The results showed that the expression of P301LTau protein in MEC could induce cognitive impairment in mice one month after the expression of P301LTau protein, but the overexpression of Tau40 protein in MEC did not cause cognitive impairment in mice for one month. The overexpression of P301 LTau protein in MEC for one month resulted in excessive phosphorylation of Tau protein. The decrease of synaptic plasticity and the decrease of neuronal activity could significantly inhibit the neuronal activity one month after Tau40. Overexpression of Tau40 in MEC for 3 and 6 months caused a decrease in olfactory dependent memory, but spatial memory was not impaired. The spread of Tau protein occurs within three months after the overexpression of Tau40 in MEC. Recent studies have shown a link between dementia and hypotension. How hypotension increases the risk of Alzheimer's disease (AD) is unclear. In adult Sprague-Dawley (SD) rats, an overdose of angiotensin 鈪，

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