本文選題：老年癡呆癥 + 神經(jīng)元活性　； 參考：《華中科技大學(xué)》2014年博士論文

【摘要】：阿爾茨海默氏病(AD)至關(guān)重要的特征性病理改變之一是異常改變的微管相關(guān)Tau蛋白選擇性在不同類型的神經(jīng)細(xì)胞內(nèi)形成神經(jīng)纖維纏結(jié)。根據(jù)Braak分期,內(nèi)嗅皮層是最早出現(xiàn)異常Tau蛋白的皮層,并且一些影像學(xué)結(jié)果也顯示了神經(jīng)元活性的下降與Braak分期一致。為了解異常Tau蛋白對(duì)神經(jīng)元活性的影響,我們?cè)谛∈蟮闹袃?nèi)嗅皮層(Media entorhinal cortex, MEC)表達(dá)P301LTau或過(guò)表達(dá)人Tau40蛋白來(lái)模擬早期AD病人。結(jié)果發(fā)現(xiàn),在MEC表達(dá)P301LTau蛋白一個(gè)月后可以引起小鼠認(rèn)知障礙,而在MEC過(guò)表達(dá)Tau40一個(gè)月不會(huì)引起小鼠認(rèn)知障礙。MEC表達(dá)P301LTau蛋白一個(gè)月后可引起Tau蛋白過(guò)度磷酸化、突觸可塑性下降以及神經(jīng)元活性的下降；MEC過(guò)表達(dá)Tau40一個(gè)月后可明顯抑制神經(jīng)元活性。在MEC過(guò)表達(dá)Tau40三個(gè)月及六個(gè)月可引起依賴嗅覺(jué)的記憶下降,但空間記憶沒(méi)有受損。在MEC過(guò)表達(dá)Tau40三個(gè)月即出現(xiàn)Tau蛋白的傳播。 近來(lái)研究結(jié)果表明癡呆和低血壓之間有相關(guān)性。低血壓是如何增高老年癡呆(AD)風(fēng)險(xiǎn)的機(jī)制尚不清楚。我們對(duì)成年Sprague-Dawley (SD)大鼠給予過(guò)量的血管緊張素Ⅱ一型受體(AT1)抑制劑氯沙坦一個(gè)月后能夠引起慢性、持續(xù)性低血壓,并伴隨有氧化應(yīng)激反應(yīng)。而且,我們發(fā)現(xiàn)氯沙坦導(dǎo)致非激活形式的PP2A水平上升,Tau蛋白的Ser199和Ser396位點(diǎn)出現(xiàn)過(guò)度磷酸化。給予氯沙坦的大鼠表現(xiàn)出記憶缺陷和大腦皮層樹(shù)突棘密度的下降。這些結(jié)果表明過(guò)量氯沙坦引起的低血壓可能通過(guò)氧化應(yīng)激導(dǎo)致Tau蛋白過(guò)度磷酸化和樹(shù)突棘丟失,從而增加了AD樣病理改變和行為學(xué)異常的風(fēng)險(xiǎn)。 阿爾茲海默病(AD)是最常見(jiàn)的神經(jīng)退行性疾病,絕大多數(shù)AD病人都是晚發(fā)散發(fā)形式。所以,研究環(huán)境因素是如何影響和促進(jìn)AD的發(fā)病具有重要意義。目前,社會(huì)隔離(social isolation, SI)這種環(huán)境因素對(duì)野生型小鼠認(rèn)知的影響尚不清楚。SI是否會(huì)引起腎上腺素能信號(hào)通路改變,SI與AD的發(fā)病機(jī)制的關(guān)系也不清楚。為了研究上述問(wèn)題,我們將剛斷奶的3周齡小鼠進(jìn)行SI喂養(yǎng)6周,結(jié)果發(fā)現(xiàn)SI小鼠依賴杏仁核的條件恐懼記憶下降并伴隨焦慮情緒出現(xiàn),同時(shí)依賴海馬的空間學(xué)習(xí)能力下降。SI小鼠腎上腺素能信號(hào)通路激活,淀粉樣前體蛋白(APP)淀粉樣剪切途徑被激活并導(dǎo)致Aβ40的表達(dá)增高。SI的突觸可塑性受到了明顯的抑制。用βR抑制劑普萘洛爾喂養(yǎng)SI小鼠可以改善SI小鼠的認(rèn)知障礙。
[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，

本文編號(hào)：2101532