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Title: | YC-1對Aβ誘導之神經毒性的保護作用之探討 Protective effects of YC-1 against Aβ-induced neurotoxicity |
Authors: | Tzu-Kwan Yang 楊子寬 |
Advisor: | 符文美(Wen-Mei Fu) |
Keyword: | 阿茲海默氏症,β-澱粉樣蛋白(Aβ),oligomers,YC-1,神經保護,熱休克蛋白70 (HSP70), Alzheimer's disease,β- amyloid (Aβ),oligomers,YC-1,neuroprotective effect,heat shock protein 70 (HSP70), |
Publication Year : | 2015 |
Degree: | 碩士 |
Abstract: | 阿茲海默氏症是一種、發病進程緩慢的神經退化性疾病,此疾病會導致認知功能障礙。阿茲海默氏症在病理上的特徵是由異常聚集的β-澱粉樣蛋白(Aβ)所造成。Aβ會誘發神經突觸毒性,造成神經突觸損失和神經細胞死亡,最終造成記憶功能下降。近來許多的證據指出,oligomerized Aβ胜肽是主要產生毒性的元兇,它會對神經突觸造成損害,影響神經網絡的正常運作。因此, Aβ逐漸成為阿茲海默氏症的診斷標誌物和治療的研究標的。
本篇研究目的是探究YC- 1對於Aβ誘導的毒性是否具有神經保護作用以及其潛在的保護機制。YC-1是benzyl indazole的衍生物,具有多方面的藥理作用,例如其能活化鳥苷酸環化酶(sGC)以及抑制缺氧誘導因子1α(HIF-1α)。在本篇研究中,我們在初代海馬迴神經元培養以oligomeric Aβ誘發毒性。發現oligomeric Aβ會導致神經樹突的損失並造成細胞存活率下降,而這些現象會因為伴隨給予YC-1或其前驅物而被拮抗。我們接著進一步探究YC-1及其前驅物在對抗Aβ所誘導之毒性的神經保護效果與機制。研究結果顯示,YC-1及其前驅物的神經保護作用,會因為給予HSP70抑制劑而被拮抗。 在本篇研究中,由腦室內(i.c.v.)給藥的途徑,以被動迴避試驗評估小鼠的學習記憶功能更進一步探究了YC-1對Aβ的急性保護神經效果。我們發現在給予Aβ後,明顯造成小鼠記憶力變差,而伴隨YC-1或其前驅物的給予皆能顯著地減緩Aβ使小鼠記憶力變差的作用。此外,我們還檢視了小鼠的皮質區域和海馬迴區域一些突觸蛋白的表現量。Aβ造成了一些麩氨酸受體的表現量明顯減少,例如NMDA受體分類中的NR1和NR2B亞型受體、AMPA受體分類中的GluR1亞型受體、和mGluR5受體。其他突觸蛋白,例如neuroligin1(NLGN1)和synapsin的表現量也有明顯的減少。而伴隨給予YC-1或其前驅物,皆顯著增加了蛋白的表現量,這個結果顯示,YC-1及其前驅物對於Aβ所誘導之神經元損傷具有保護作用。 綜合以上的結論,Aβ oligomers誘導之神經樹突損失和神經元死亡,可以透過給予YC-1或其前驅物來保護,其神經保護作用的機制可能部分與HSP70的參與有關。急性腦室內給予可溶性Aβ oligomers造成了小鼠顯著的記憶喪失,並且,在皮質區域和海馬迴區域,皆造成突觸蛋白的減少,而伴隨給予YC-1或其前驅物能顯著減緩記憶喪失及拮抗突觸蛋白的減少。我們的結果顯示,YC-1及其前驅物,不論是在體外和體內實驗,皆對Aβ所誘導的神經毒性扮演著神經保護的角色。 Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to debilitating cognitive deficits. Aggregates of amyloid-beta (Aβ) are the major pathological hallmark of AD which leads to synaptic toxicity and results in synaptic loss, neuronal death and eventually memory dysfunction. Emerging evidence suggests that soluble oligomerized Aβ peptides are the principal neurotoxic agents that contribute to synaptic damage, resulting in dysfunctional neuronal networks in AD patients. Therefore, Aβ has become a popular target for the therapeutic interventions and diagnostic marker for AD. The aim of this study is to investigate whether YC-1 exerts neuroprotective effect against Aβ-induced toxicity and its potential mechanisms. YC-1, a derivative of benzyl indazole, possesses various pharmacological actions, such as the activation of soluble guanylyl cyclase (sGC) and the inhibition of hypoxia-induced factor-1α (HIF-1α). Here we found that exposure of primary hippocampal neuronal cultures to Aβ1-42 oligomers significantly led to dendritic loss and decreased cell viability, which was rescued by concomitant treatment of YC-1 or its precursor. We thus investigated the possible mechanisms for the protective effect of YC-1. Our results showed that concomitant treatment of HSP70 inhibitor antagonized the neuroprotective effect of YC-1 and its precursor. Following intracerebroventricular (i.c.v.) administration of Aβ oligomers, we assessed the acute neuroprotective effect of YC-1 or its precursor on memory function using the passive avoidance test in mice. Aβ treatment significantly led to memory impairment, which was reversed by concomitant treatment of YC-1 or its precursor. Moreover, we examined the expression of some synaptic proteins from cortex and hippocampus regions of mice. Aβ treatment significantly reduced the expression of some glutamate receptors, such as the NR1 and NR2B subunit of NMDA receptors, GluR1 subunit of AMPA receptors and mGluR5 receptor. The expression of other synaptic proteins such as neuroligin 1(NLGN1) and synapsin was also reduced. Concomitant treatment of YC-1 or its precursor both markedly inhibited Aβ-induced synaptic loss, indicating the protective effect against Aβ-induced neuronal damage. In conclusion, Aβ oligomer treatment significantly reduced dendritic density, resulted in slender dendrites and also neuronal cell death, which were attenuated by concomitant treatment of YC-1 or its precursor, and HSP70 may be involved in the neuroprotective effect of YC-1 or its precursor. Acute intracerebroventricular (i.c.v.) administration of soluble Aβ oligomers induced significant memory loss and certain synaptic protein loss in cortex and hippocampus region of mice, which could be antagonized by YC-1 or its precursor. Our results demonstrated that YC-1 or its precursor plays a neuroprotective role against Aβ-induced neurotoxicity both in vitro and in vivo. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/53159 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 藥理學科所 |
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