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系統識別號 U0026-1601201210341600
論文名稱(中文) 離群索居的阿茲海默氏老鼠會加速減弱海馬迴長期增益現象和損傷空間恐懼記憶
論文名稱(英文) Acceleration of rundown of hippocampal long-term potentiation and impairment of contextual fear memory by social isolation in a mouse model of Alzheimer’s disease
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 100
學期 1
出版年 101
研究生(中文) 蕭雅心
研究生(英文) Ya-Hsin Hsiao
學號 s5896127
學位類別 博士
語文別 英文
論文頁數 126頁
口試委員 指導教授-簡伯武
召集委員-司君一
口試委員-曾淑芬
口試委員-陳舜華
口試委員-符文美
口試委員-曾清俊
中文關鍵字 離群索居  阿茲海默氏症 
英文關鍵字 social isolation  Alzheimer’s disease 
學科別分類
中文摘要 流行病學研究顯示離群索居(social isolation)者有增加失智的風險。研究依照三個特定目標來進行實驗:(1)探索離群索居影響Aβ沈積和阿茲海默氏症動物模式認知損害嚴重性的分子機制為何。(2) 評量抗氧化物質N-acetylcysteine (NAC)如何回復APP/PS1老鼠因離群索居惡化阿茲海默氏症發展的現象。(3) 檢測陪伴是否有助於延緩阿茲海默氏症的發展。我們將帶有澱粉樣蛋白前驅蛋白(Amyloid precursor protein; APP)和presenilin 1 (PS1)的基因轉殖鼠,在初生後28天,隨機分成獨居與群居兩組,等待APP/PS1老鼠長至三個月大時再以恐懼制約模式進行認知記憶評估。在第一部份研究,我們發現離群索居的3個月大APP/PS1老鼠會加速惡化空間恐懼記憶以及海馬迴長期增益現象。海馬迴Aβ 含量明顯增加在離群索居的APP/PS1老鼠並且伴隨著有增高calpain活性和p25/p35比例的現象。除此之外,在離群索居的APP/PS1老鼠,突觸表面GluR1是減少的,並且相較於其他組別,p35-GluR1-CaMKII的連結明顯減弱。這些結果證實離群索居加速記憶損傷是藉由增加Aβ含量,導致calpain活性增加,將p35切割成p25,減少p35-GluR1-CaMKII的結合,造成突觸表面AMPAR減低的現象。而第二部分研究,我們調查離群索居加速記憶損傷是否是由於氧化壓力所引起的。在此部分的研究結果顯示,抗氧化藥物NAC,能夠改善離群索居的APP/PS1老鼠恐懼記憶以及海馬迴長期增益現象惡化的情況。其改善的功能是透過降低海馬迴γ-secretase活性,減少Aβ42和Aβ40含量。除此之外,NAC能使APP/PS1老鼠因離群索居所引發的calpain活性和p25/p35比例增加,以及膜上p35和p35/Cdk5活性減低的情形回復至正常狀態。同時NAC的給予也反轉APP/PS1老鼠因離群索居所引起的GluR1 Ser831磷酸化,突觸表面AMPARs和p35-GluR1-CaMKII減弱的情形。而NAC給予減弱γ-secretase活性,特別是作用在Aph1B,而此現象會因p35 shRNA的給予喪失其抑制作用。這些結果意味著,NAC降低γ-secretase活性,減弱Aβ生成和calpain活化,減少p35反轉成p25藉此穩定p35與GluR1-CaMKII的結合,可回復突觸表面GluR1和GluR2的表現。我們的研究顯示在阿茲海默氏症的動物模式上,NAC具有改善認知功能的效果,並且有潛力運用於治療人類的失智症。最後一部份研究則是探討是否陪伴有助於抑制阿茲海默氏症發展。實驗結果發現,相較於其他陪伴年齡的老鼠,給予1個月大的WT陪伴老鼠會使得年老的APP/PS1老鼠記憶改善情形較為明顯。所以我們選用1個月大的WT老鼠當陪伴模式,我們依據記憶有無改善,將年老的APP/PS1老鼠區分成對陪伴無作用以及敏感兩組。此部分實驗結果顯示,相較於9個月大(控制組)以及無改善組,對於陪伴有作用的APP/PS1老鼠其Aβ42/Aβ40 比例與 calpain活性有明顯降低的現象。並且在未來我們將著手研究年老的APP/PS1老鼠與陪伴老鼠之間的互動情況,並探究互動情形與阿茲海默氏症發展有何關連性以及參與其中機制為何。
英文摘要 Epidemiological study reveals that socially isolated persons have increased risk of developing Alzheimer’s disease (AD). The aims of research are following: (1) to investigate the cellular mechanisms of how social isolation influenced amyloid β peptide (Aβ) accumulation and affected the severity of AD-associated cognitive decline in a mouse model of AD. (2) to evaluate how N-acetylcysteine (NAC) rescue social isolation-aggravated the progression of AD in APP/PS1 mice. (3) to detect whether companion retards AD development in APP/PS1 mice. Amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice were placed either in isolation or in group from postnatal day 28 and tested for cognitive performance at the age of 3 months with fear conditioning paradigms. In first part study, we found that social isolation-induced accelerated impairment of contextual fear memory and rundown of hippocampal LTP in 3-month old APP/PS1 mice. Hippocampal level of Aβ was significantly elevated in the isolated APP/PS1 mice which was accompanied by an increased calpain activity and p25/p35 ratio. In addition, surface expression of GluR1 subunit of AMPA receptor was decreased by social isolation. The association of p35, and α-CaMKII was significantly less in the isolated APP/PS1 mice indicating that their interaction was impaired. These results suggest that social isolation exacerbates memory deficit by increasing Aβ level, leading to the increased calpain activity, conversion of p35 to p25 and decrease in association of p35, α-CaMKII and GluR1, resulting in the endocytosis of AMPA receptors. In second part research, we investigated whether this risk arises from an oxidative stress. Here we show that NAC, an anti-oxidant, is capable of preventing social isolation-induced accelerated impairment of contextual fear memory and rundown of hippocampal LTP in 3-month old APP/PS1 mice. Increased hippocampal levels of γ-secretase acivity, Aβ-40 and Aβ-42 seen in the isolated APP/PS1 mice were reduced by chronic treatment of NAC. In addition, social isolation-induced increase in calpain activity and p25/p35 ratio concomitant with decrease in membrane-associated p35 and p35/Cdk5 activity was normalized by NAC. NAC pretreatment also reversed isolation-induced decrease in GluR1 Ser831 phosphorylation, surface expression of AMPARs and p35-GluR1-CaMKII interactions. NAC treatment also decreased γ-secretase activity especially Aph1B that reversed by p35 shRNA. These results suggest that NAC decreases γ-secretase activity resulting in the attenuation of Aβ production, calpain activity and conversion of p35 to p25 which stabilized p35-GluR1-CaMKII interactions and restored GluR1 and GluR2 surface expression. Our results indicate that NAC is effective in mouse models of AD and has translation potential for the human disorder. Finally, we evaluated whether companion helps inhibition of AD development. We found that improved ratio was higher by companion with 1-month WT mice than other groups. Then, we choose 1-month WT mice as our companion model. We divided bad or good memory of aged APP/PS1 mice as unsusceptible or susceptible to companion group. The results show that Aβ42/Aβ40 ratio and calpain activity were significantly lower in the susceptible APP/PS1 mice than in the 9-month (control) and unsusceptible groups. In the further, we will detect the correlation between social interaction and AD development and identify the mechanism of social network.
論文目次 Abbreviations………………………………………………………………………1

Chapter 1 Introduction………………………………………………………….3
1.1. Background……………………………………………………………………4
1.2. The aim of the research…………………………………………………….....8

Chapter 2…………………………………………………………………………..11
The involvement of Cdk5 activator p35 in social isolation-triggered onset of early Alzheimer’s disease-related cognitive deficit in the transgenic mice.
2.1. Introduction………………………………………………………………12
2.2. Materials and methods………………………………………………...15
2.2.1. Animals………………………………………………………………15
2.2.2. Fear conditioning……………………………………………………15
2.2.3. Electrophysiological recordings……………………………………17
2.2.4. Aβ ELISA assay………………………………………………….….18
2.2.5-, -, and -secretase activity……………………………………...18
2.2.6. Western blotting and immunoprecipitation…………………….…19
2.2.7. Cdk5 Kinase assay……………………………………………….….20
2.2.8. Surface biotinylation assay…………………………………………21
2.2.9. Calpain activity……………………………………………………...22
2.2.10. Surgery……………………………………………………………..22
2.2.11. shRNA virus production…………………………………………..22
2.2.12. Statistical Analysis…………………………………………………23
2.3. Results……………………………………………………………………...24
2.3.1. Social isolation facilitates impairment of contextual fear memory and LTP in APP/PS1 mice…………………………………………..24
2.3.2. Social isolation increases hippocampal levels of Aβ40 and Aβ42 in APP/PS1 mice……………………………………………………….26
2.3.3. Social isolation has no effect on Insulin-degrading enzyme and neprilysin ……………………………………………………………27
2.3.4. Social isolation enhances the conversion of p35 to p25…………...27
2.3.5. Social isolation increases calpain activity in APP/PS1 mice…………………………………………………………………..28
2.3.6. Social isolation decreases p35 via ubiquitin-proteasome pathway……………………………………………………………...29
2.3.7. p35 is involved in isolation-induced acceleration of cognition impairment…………………………………………………………..30
2.3.8. Social isolation decreases surface expression of AMPARs……….31
2.3.9. The expression of p35 and surface GluR1 are decreased in aged APP/PS1 mice……………………………………………………….32
2.4. Discussion…………………………………………………………………34
2.4.1. Acceleration of memory impairment by social isolation………….34
2.4.2. Linking A to p35 and memory impairment……………………...36
2.5. Figure legend……………………………………………………………..39

Chapter 3…………………………………………………………………………..50
Amelioration of social isolation-triggered onset of early Alzheimer’s disease-related cognitive deficit by N-acetylcysteine in a transgenic mouse model
3.1. Introduction………………………………………………………………51
3.2. Materials and methods………………………………………………...54
3.2.1. Animals………………………………………………………………54
3.2.2. Fear conditioning……………………………………………………54
3.2.3. Electrophysiological recordings……………………………………56
3.2.4. Aβ ELISA assay………………………………………………….….56
3.2.5-, -, and -secretase activity……………………………………...57
3.2.6. RT-PCR……………………………………………………………...57
3.2.7. Western blotting assay……………………………………………...58
3.2.8. Immunoprecipitation assay………………………………………...59
3.2.9. Surface biotinylation assay…………………………………………60
3.2.10. p35/ Cdk5 Kinase assay…………………………………………...61
3.2.11. Measurement of antioxidant activity………………………….….61
3.2.12. Surgery………………………………………………………….….62
3.2.13. shRNA virus production……………………………………….….63
3.2.14. Calpain activity………………………………………………….…64
3.2.15. Statistical Analysis…………………………………………………64
3.3. Results………………………………………………………………….…..65
3.3.1. Reversal of isolation-induced contextual memory impairment by NAC………………………………………………………………….65
3.3.2. Recovery of isolation-induced impairment of LTP by NAC……...67
3.3.3. Effects of NAC on social isolation-induced increase in hippocampal A levels……………………………………………………………...67
3.3.4. Involvement of p35 in the reversal effect of NAC on memory impairment…………………………………………………………..69
3.3.5. NAC treatment on caplain activity in isolated APP/PS1 mice…...70
3.3.6. The effect of NAC is blocked by PKC shRNA…………………...71
3.3.7. Social isolation decreases surface expression of AMPARs……….71
3.3.8. NAC affects p35 association with GluR1, GluR2, and -CaMKII…………………………………………………………...73
3.3.9. NAC treatment decreases Aph1B -secretases in isolated APP/PS1 mice…………………………………………………………………..73
3.4. Discussion…………………………………………………………………75
3.4.1. NAC reduces social isolation-induced increase in hippocampal levels of A-40 and A-42…………………………………………..75
3.4.2. p35 and memory impairment………………………………………76
3.5. Figure legend……………………………………………………………..79

Chapter 4…………………………………………………………………………..93
Companion improves AD development in aged APP/PS1 mice.
4.1. Introduction………………………………………………………………94
4.2. Materials and methods………………………………………………...96
4.2.1. Animals………………………………………………………………96
4.2.2. Fear conditioning……………………………………………………96
4.2.3. Aβ ELISA assay……………………………………………………..97
4.2.4. Calpain activity……………………………………………………...98
4.2.5. Statistical Analysis…………………………………………………..98
4.3. Results……………………………………………………………………...99
4.3.1. Companion affects fear memory…………………………………...99
4.3.2. To divide bad or good memory as unsusceptible or susceptible to companion…………………………………………………………...99
4.3.3. Companion decreases Aβ42 /Aβ40 ratio in susceptible group……100
4.3.4. Susceptible to company group ameliorates memory impairment by regulation of calpain activity……………………………………..100
4.4. Discussion……………………………………………………………….101
4.5. Figure legend…………………………………………………………...103

Chapter 5…………………………………………………………………………109
Conclusion

References………………………………………………………………………..112
Curriculum vitae……………………………………………………………….122
List of figures……………………………………………………………………124
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