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系統識別號 U0026-1108201423105000
論文名稱(中文) 能量不足對乙型類澱粉蛋白的累積與tau蛋白磷酸化之影響
論文名稱(英文) Effect of energy deficiency on the accumulation of Aβ and phosphorylation of tau
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 102
學期 2
出版年 103
研究生(中文) 李竹菀
研究生(英文) Chu-Wan Lee
學號 s58951340
學位類別 博士
語文別 英文
論文頁數 78頁
口試委員 指導教授-郭余民
召集委員-任卓穎
口試委員-司君一
口試委員-許桂森
口試委員-施能耀
口試委員-林靜茹
中文關鍵字 阿茲海默氏症  乙型類澱粉蛋白  磷酸化tau蛋白  能量不足 
英文關鍵字 Alzheimer’s disease  β-Amyloid  hyperphosphorylated tau proteins  energy deficiency 
學科別分類
中文摘要 阿茲海默氏症是一種認知功能逐漸退化的老年疾病。主要的病理特徵為神經細胞內tau蛋白的過度磷酸化導致神經纖維化糾結,和細胞外乙型類澱粉蛋白(Aβ)聚集形成之類澱粉斑塊。流行病學與病理學的研究顯示,心血管疾病是阿茲海默氏症的重要危險因子。已知器官低灌流(hypoperfusion)與能量不足,是眾多心血管疾病的共通因子。但是,能量代謝異常是否會直接影響阿茲海默氏症的病理形成,至今仍不清楚。為了探討能量不足與阿茲海默氏症病理的因果關係,我們進行以下三個實驗。(一)把分化後之neuron 2a (N2a)神經母細胞培養於無糖的培養液中,使其粒線體膜電位下降,而細胞能量感應器-腺苷激活蛋白激酶(AMPK)的活化程度上升。此時,其tau蛋白的磷酸化程度會上升,且磷酸化tau蛋白的糖原合成酶激酶(GSK3)的活化程度也上升。(二)接著我們在Wistar大鼠腦中注射鏈佐黴素(Streptozotocin,STZ),用以傷害表現葡萄糖轉運子-2的星狀膠細胞,藉此阻斷葡萄糖從血管傳送到神經細胞的路徑。結果顯示,腦內注射STZ的大鼠,其AMPK與GSK3的活化程度上升,tau蛋白磷酸化的程度增加,而學習記憶的能力下降。由於N2a神經細胞和Wistar大鼠腦中Aβ的表現量很低,無法準確量測,所以我們(三)另外選用大量表現人類乙型類澱粉前驅蛋白的N2a神經細胞 (APP細胞),來研究能量不足是否會影響Aβ的表現。結果顯示,培養於無糖培養液中的APP細胞,其AMPK的活化程度上升,Aβ的表現量則下降。我們還發現,Aβ的表現量與培養液中葡萄糖的量成正比,但與AMPK的活化程度成反比。如果APP細胞培養在含有葡萄糖的培養液中,並給予AMPK的活化劑,則Aβ的濃度會降低。但是,如果APP細胞培養在無糖培養液中,並給予AMPK的抑制劑,則Aβ的濃度會大幅增加,但是其他APP代謝產物的濃度則不變。總結本研究,我們發現能量不足時,tau蛋白磷酸化的程度會增加,此時如果AMPK的活化被抑制,則可能透過抑制Aβ的清除而增加其濃度。所以,能量代謝不足會促進阿茲海默氏症病理的進程。
英文摘要 Alzheimer’s disease (AD) is an age-related neurodegenerative disease. AD occurs gradually and results in memory loss, behavior and personality changes, and a decline in thinking abilities. Pathologically, AD is characterized by intracellular aggregation of neurofibrillary tangles and extracellular deposition of amyloid plaque. The amyloid plaques primarily consist of β-Amyloid (Aβ) peptides and the neurofibrillary tangles comprise of hyperphosphorylated tau proteins. Results from epidemiological and pathological research showed a strong link between cardiovascular diseases and AD. It has been suggested that chronic brain hypoperfusion is the common denominator among cardiovascular diseases. One major consequence of hypoperfusion is insufficient supply of glucose to brain, hence results in cerebral hypometabolism. However, whether energy deficiency contributes to the development of AD remains unclear. To investigate the causal relationship, we performed the following three experiments. 1) We cultured the differentiated N2a neuroblastoma cells in media containing no glucose or pyruvate (NGM). Shortly after the N2a cells cultured in the NGM, the mitochondria membrane potential was reduced and the AMP-activated-protein-kinase (AMPK), an energy sensor, was activated. Treatment of NGM not only increased the levels of tau phosphorylation at Ser262 and Ser396, but also increased the levels of active forms of GSK3α and GSK3β, two major tau kinases. 2) The effect of energy deficiency was further examined in vivo by intracerebroventricular (icv) injection of streptozotocin (STZ) to the Wistar rats. STZ selectively injuries glucose transporter type 2-bearing cells which are primarily astrocytes in the rat brain, hence, interrupts glucose transportation from blood vessel to neuron. STZ-icv injection induced energy crisis in the brain regions surrounding the ventricles, as indicated by elevated pAMPK levels in the hippocampus. STZ-icv treatment increased the levels of phosphorylated tau and activated GSK3β in the hippocampus. The hippocampus-dependent spatial learning and memory was impaired by the STZ-icv treatment. 3) Because the levels of Aβ in the N2a cells and Wistar rats were too low to be accurately quantified, we therefore used human amyloid precursor protein overexpressed N2a cells (APP cells) to investigate the effect of energy deficiency on Aβ production. The results showed that concentrations of glucose in culture media negatively associated with the levels of pAMPK in the APP cells, but positively correlated with the levels of Aβ in the condition media. When APP cells were cultured in glucose-containing media, drug-induced activation of AMPK decreased the levels of Aβ in the condition media. However, if APP cells were incubated in media containing no glucose, inhibition of AMPK activity increased the levels of Aβ, while the levels of full-length APP, APPα, APPβ, APP C-terminal fragment α and C-terminal fragment β were unchanged. Taken together, these studies suggest that energy deficiency increases the levels of tau phosphorylation. Furthermore, when energy is deficient and AMPK activation is inhibited, the levels of Aβ are increased, probably due to reduced clearance of Aβ. Thus, our studies support the premise that metabolic disorders contribute to AD pathogenesis.
論文目次 中文摘要....................................................I
Abstract..................................................II
誌謝......................................................IV
Contents..................................................VI
Figure Contents.........................................VIII
I. Introduction............................................1
1. Alzheimer’s disease (AD)................................1
2. AD and metabolic abnormality............................4
2.1. Diabetes mellitus (DM)................................4
2.2. Obesity...............................................5
2.3. Cardiovascular diseases (CVDs)........................5
3. AD, metabolic abnormality and hypoperfusion.............7
4. Metabolic abnormality and AMP-activated-protein-kinase (AMPK).....................................................8
5. Streptozotocin (STZ)....................................8
II. Hypothesis and Specific Aims..........................10
III. Experimental designs.................................11
Aim 1: Study the effect of energy deficiency on tau phosphorylation and Aβ production in vitro................11
Aim 2: Characterize the effect of energy deficiency on tau phosphorylation and Aβ production in animals..............11
Aim 3: Characterize the effect of energy deficiency on APP metabolism in APP-overexpression cells....................11
Aim 4: Characterize the role of AMPK in APP metabolism in APP-overexpression cells..................................11
IV. Materials and Methods.................................12
1. Cell culture...........................................12
2. Mitochondrial membrane potential.......................13
3. Cell viability assay...................................13
4. Drug treatments........................................14
5. Immunoprecipitation (IP)...............................14
6. Western blot...........................................15
7. Animals................................................16
8. Intracerebroventricular (icv) injection of STZ.........17
9. Brain processing.......................................17
10. Immunohistochemistry..................................17
11. Morris Water Maze.....................................18
12. Statistical analysis..................................18
V. Results................................................20
1. Glucose deficiency reduces mitochondria membrane potential and induces AMPK activation.....................20
2. Glucose deficiency activates the Akt-GSK3 signaling pathway and increases tau phosphorylation.................20
3. STZ-icv injection does not change peripheral blood glucose levels or brain weight in rats....................21
4. STZ-icv injection induces energy deficiency in rats....21
5. STZ-icv injection increases tau phosphorylation in hippocampal CA region pyramidal neurons...................22
6. STZ-icv injection induces impairment in the learning and memory performance........................................22
7. STZ-icv injection dose not observe Aβ deposition.......23
8. Effects of glucose concentration on cell viability and AMPK activation...........................................23
9. Effects of glucose concentration on APP metabolism.....24
10. AMPK activation decrease Aβ production................25
11. AMPK inhibition decrease Aβ production................25
VI. Discussion............................................27
VII. Conclusion...........................................33
VIII. References..........................................34
X. Appendixes.............................................77
XI. Publications..........................................78
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