臺灣博碩士論文加值系統

阿茲海默症(Alzheimer’s disease, AD)為失憶症的一種，是現今老年失智症中為數最多的一類，在過去分子醫學的研究中， 腦部神經細胞外乙型類澱粉蛋白的堆積與腦部神經細胞內tau 蛋白不正常的纖維化，被認為是阿茲海默症兩個重要的指標。而過往的研究，也多著重在以此兩個蛋白為中心的探討，在預防的構想上，多是如何阻止其不正常堆疊或是加速其分解而延伸出的議題。近年來發現，腦部中乙型類澱粉蛋白寡聚體似乎才是關鍵，是腦部神經細胞毒性的來源，而非病人腦部常見的乙型類澱粉蛋白斑塊，這讓研究人員想得知，乙型類澱粉寡聚體是如何對神經細胞產生影響。在這幾年的研究當中，發現有些分子可能在細胞表面作為乙型類澱粉寡聚體的蛋白受器，並藉此影響神經細胞電訊號的傳遞，進而影響其正常功能，如學習記憶等，普立昂蛋白便為其中重要的一員。普立昂蛋白為一有功能的正常蛋白，其不正常摺疊可導致狂牛症，在2009 年自然期刊發表中，經由研究者大規模篩選後，發現與乙型類澱粉寡聚體有最高親和力的蛋白就是野生型的普立昂蛋白。因此，研究乙型類澱粉寡聚體透過普立昂蛋白所引發的下游訊息傳遞路徑，可讓我們對阿茲海默症的致病機制有更深入的了解。
我們發現在人類神經母細胞瘤細胞株高度表達野生型普立昂蛋白會降低tau 蛋白的表現，而乙型類澱粉寡聚體會減緩此一現象，讓tau 蛋白表現回復，此一現象不但延續2009 年自然期刊的發現，乙型類澱粉寡聚體會接合到普立昂蛋白，更進一步連結到阿茲海默症另一重要的指標，tau 蛋白。然而，若是高度表現在阿茲海默病人中比例較高之普立昂點突變M128V 型蛋白時，則tau 蛋白表現下降的情形，便不受乙型類澱粉寡聚體調控。另一方面，若是表現去除普利昂蛋白上乙型類澱粉寡聚體的相互作用序列胺基酸95-110 之缺陷型蛋白，則tau 蛋白的表現也不受調控。我們發現對於tau 蛋白調控是源自於轉錄其mRNA (MAPT)表現接著深入研究其中間傳遞的機制，我們發現Fyn 磷酸激酶的磷酸化與MEK 磷酸激酶在這中間扮演訊息傳遞的重要角色。整體而言，我們研究發現乙型類澱粉寡聚體接合到細胞表面普立昂蛋白後的下游機制，而了解乙型類澱粉寡聚體-普立昂蛋白-MAPT-tau 的訊息傳導路徑與Fyn、MEK 磷酸化相關。

Extracellular senile plaques composing mainly of amyloid-β (Aβ) and intracellular neurofibrillary tangles comprising misfolded and hyper-phosphorylated tau protein are pathologic hallmarks in Alzheimer’s disease (AD). Aβ aggregates are considered the toxic entities in AD in which soluble Aβ oligomers (AβOs) are shown more toxic than other Aβ species. Cellular prion protein (PrPC) is an emerging receptor that has highest binding affinity with Aβ oligomers while the relationship between PrPC and AD remains to be clarified. To inspect the downstream signal transduction pathway under the interaction of AβOs and PrPC, we examined the tau protein level by using murine PrPC-over-expressing human neuroblastoma BE(2)-C cells and the influences under Aβ42 oligomer treatment. Interestingly, down-regulation of total tau protein level was observed in PrPC-over-expressing neuroblastoma while Aβ42 oligomer treatment mitigated the PrPC WT-induced tau reduction but not PrPC M128V, the high population PrPC polymorphic allele in AD patient. The rescue effect of PrPC-induced tau reduction by Aβ42 oligomer treatment was diminished in PrPC mutant lacking the major Aβ oligomer binding site, amino acids 95-110. Quantitative PCR manifested that the tau reduction under PrPC over-expression was ascribed to transcriptional regulation. Fyn kinase and MEK inhibition by PP2 and U0126 respectively could ameliorate the PrPC-induced tau reduction, and Aβ42 oligomer treatment modulated Fyn kinase phosphorylation. These evidences revealed that Fyn signal transduction is involved in AβOs-PrPC-MAPT-tau pathway. In conclusion, we illustrated the relationship that PrPC down-regulated tau associated with Fyn pathway and AβOs can alleviate this effect. Our study facilitated the essential knowledge for the relationship of three important molecules in AD, Aβ oligomers, PrPC and tau.

Table of Contents............................................................................................................… I
List of Figures.................................................................................................................... V
Abbreviations .................................................................................................................. VII
摘要 .................................................................................................................................. IX
Abstract ............................................................................................................................ X

1. Introduction and Rationale............................................................................................. 1
1.1 Alzheimer’s disease (AD).............................................................................................. 1
1.2 Amyloid-beta (Aβ) ....................................................................................................... 2
1.3 Tau is one microtubule-associated protein (MAPT)....................................................... 4
1.4 PrPC which means the normal cellular prion protein..................................................... 5
1.5 Aβ oligomers with cellular PrPC may play a role in AD ................................................. 6
1.6 Controversial issue ...................................................................................................... 7
1.7 Rationale ..................................................................................................................... 8

2. Materials and Methods................................................................................................... 9
2.1 Aβ42 Oligomer Preparation........................................................................................... 9
2.2 Transmission Electron Microscopy (TEM) .................................................................... 10
2.3 Constructs ................................................................................................................. 10
2.4 Cellular Binding Assays of Aβ42 Oligomers ................................................................ 10
2.5 Human Neuroblastoma Cell Culture and Transfection.................................................. 12
2.6 Cell Lysis, Western Blotting Aanalysis and Image Quantification .................................. 12
2.7 Quantitative Real-time PCR (qPCR) and Data Analysis................................................... 13
2.8 Cell Viability MTT Assay .............................................................................................. 14
2.9 Cell Viability Trypan Blue Exclusion Assay.................................................................... 15
2.10 Fyn Pathway Inhibitor Treatments ............................................................................. 15
2.11 Immunoprecipitation (IP) .......................................................................................... 16
2.12 Proteasome Inhibitor Treatments.............................................................................. 16
2.13 Knockdown Assay by Short Hairpin RNAs (shRNAs)................................................... 16
2.14 Statistical Analysis.................................................................................................... 17

3. Results ......................................................................................................................................................................................................................... 18
3.1 Aβ42 Oligomer Treatment Mitigated The Cellular Tau Reduction Induced by PrPC Expression but not PrPC M128V. ................................................... 18
3.1.1 Aβ oligomer preparation for PrPC ............................................................................................................................................................................ 18
3.1.2 Tau expression and modification in PrPC over-expressing cells under Aβ42 oligomer treatment ............................................................................. 19
3.1.3 Tau expression in prion Δ95-110 over-expressing cells under Aβ42 oligomer treatment ........................................................................................ 20
3.2 The PrPC-Induced Tau Reduction Was Ascribed to Tau mRNA Downregulation and the Tau mRNA Can Be Regressed by Aβ42 Oligomer Treatment .... 21
3.2.1 Tau mRNA, MAPT expression in PrPC over-expressing cells under Aβ42 oligomer treatment .................................................................................. 21
3.2.2 Proteasome activity in PrPC over-expressing cells under Aβ42 oligomer treatment .................................................................................................. 21
3.3 Fyn Pathway Inhibition Relieved PrPC-Induced Tau Reduction. .................................................................................................................................... 22
3.3.1 Tau, Fyn and p-SFK expression in PrPC over-expressing cells with Src kinase, MEK1/2 inhibitors ............................................................................ 22
3.4 Aβ42 Oligomer Treatment Modulated Fyn Kinase Phosphorylation. ............................................................................................................................. 23
3.4.1 Fyn and p-SFK expression in PrPC over-expressing cells with Aβ42 oligomer treatment .......................................................................................... 23

4. Discussion ..................................................................................................................... 24
4.1 The toxic entities of Aβ oligomers with PrPC ................................................................ 24
4.2 The M129V polymorphism of PrPC ............................................................................... 24
4.3 The 95-110 fragment of PrPC....................................................................................... 25
4.4 The lose-of-function of PrPC in AD............................................................................... 25
4.5 The transcriptional regulation of PrPC .......................................................................... 26
4.6 PrPC and Fyn................................................................................................................. 26
4.7 Fyn and MEK inhibition under PrPC over-expression..................................................... 27
4.8 Fyn phosphorylation under Aβ oligomers ..................................................................... 27
4.9 Fyn degradation under proteasome inhibitor................................................................. 28
4.10 Transcription factors between Fyn and MAPT ............................................................. 28
4.11 Many faces of bi-function tau .................................................................................... 29
4.12 The signal transduction pathway ................................................................................ 30

References ......................................................................................................................... 31
Figures .............................................................................................................................. 40
Appendix ........................................................................................................................... 52

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