Understanding amyloid-beta and amyloid precursor protein in Alzheimer’s disease with characterization of Amyloid-β A2 Variant effect and cell surface gangliosides
博士 === 國立陽明大學 === 微生物及免疫學研究所 === 105 === Alzheimer’s disease (AD) is the most common dementia affecting tens of million people worldwide. The primary neuropathological hallmark in AD is amyloid plaques composed of amyloid-β peptide (Aβ). Several familial mutations found in Aβ sequence result in earl...
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ndltd-TW-105YM0053800052017-10-14T04:28:36Z http://ndltd.ncl.edu.tw/handle/34549949595275845760 Understanding amyloid-beta and amyloid precursor protein in Alzheimer’s disease with characterization of Amyloid-β A2 Variant effect and cell surface gangliosides 藉由乙型類澱粉蛋白A2變體的影響及細胞上的神經節脂了解在阿茲海默症中乙型類澱粉蛋白及類澱粉蛋白前驅物的特性 Tien-Wei Lin 林天偉 博士 國立陽明大學 微生物及免疫學研究所 105 Alzheimer’s disease (AD) is the most common dementia affecting tens of million people worldwide. The primary neuropathological hallmark in AD is amyloid plaques composed of amyloid-β peptide (Aβ). Several familial mutations found in Aβ sequence result in early onset of AD. Previous studies showed that the mutations located at N-terminus of Aβ, such as the English (H6R) and Tottori (D7N) mutations, promote fibril formation and increase cytotoxicity. However, A2T mutant located at the very N-terminus of Aβ shows low-prevalence incidence of AD, whereas, another mutant A2V causes early onset of AD. To understand the molecular mechanism of the distinct effect and develop new potential therapeutic strategy, here, we examined the effect of full-length and N-terminal A2V/T variants to wild type (WT) Aβ40 by fibrillization assays and NMR studies. We found that full-length and N-terminal A2V accelerated WT fibrillization and induced large chemical shifts on the N-terminus of WT Aβ, whereas, full-length and N-terminal A2T retarded the fibrillization. We further examined the inhibitive effect of various N-terminal fragments (NTFs) of A2T to WT Aβ. The A2T NTFs ranging from residue 1 to residue 7 to 10, but not 1 to 6 or shorter, are capable to retard WT Aβ fibrillization and rescue cytotoxicity. The results suggest that in the presence of full-length or N-terminal A2T can retard Aβ aggregation and specific A2T NTFs can mitigate its toxicity. Our results provide a novel targeting site for future therapeutic development of AD. Beside, gangliosides play an important role in regulating neuronal function and are directly involved in AD pathology. Different contents of ganglioside molecules modulated the amyloid precursor protein (APP) processing by direct or indirect effect. However, the molecular mechanisms linking gangliosides variation with APP expression are still unknown. In this study, we used APP isoforms 770, 751, and 695 stable lines and knockdown APP by siRNA to examine the cell surface ganglioside alteration. Furthermore, APP is cleaved to produce Aβ and the APP intracellular domain (AICD) by β and γ-secretase. The result of ganglioside change may be associated with AICD-meditated effect, not Aβ monomer. Yun-Ru Chen 陳韻如 2017 學位論文 ; thesis 96 en_US |
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博士 === 國立陽明大學 === 微生物及免疫學研究所 === 105 === Alzheimer’s disease (AD) is the most common dementia affecting tens of million people worldwide. The primary neuropathological hallmark in AD is amyloid plaques composed of amyloid-β peptide (Aβ). Several familial mutations found in Aβ sequence result in early onset of AD. Previous studies showed that the mutations located at N-terminus of Aβ, such as the English (H6R) and Tottori (D7N) mutations, promote fibril formation and increase cytotoxicity. However, A2T mutant located at the very N-terminus of Aβ shows low-prevalence incidence of AD, whereas, another mutant A2V causes early onset of AD. To understand the molecular mechanism of the distinct effect and develop new potential therapeutic strategy, here, we examined the effect of full-length and N-terminal A2V/T variants to wild type (WT) Aβ40 by fibrillization assays and NMR studies. We found that full-length and N-terminal A2V accelerated WT fibrillization and induced large chemical shifts on the N-terminus of WT Aβ, whereas, full-length and N-terminal A2T retarded the fibrillization. We further examined the inhibitive effect of various N-terminal fragments (NTFs) of A2T to WT Aβ. The A2T NTFs ranging from residue 1 to residue 7 to 10, but not 1 to 6 or shorter, are capable to retard WT Aβ fibrillization and rescue cytotoxicity. The results suggest that in the presence of full-length or N-terminal A2T can retard Aβ aggregation and specific A2T NTFs can mitigate its toxicity. Our results provide a novel targeting site for future therapeutic development of AD.
Beside, gangliosides play an important role in regulating neuronal function and are directly involved in AD pathology. Different contents of ganglioside molecules modulated the amyloid precursor protein (APP) processing by direct or indirect effect. However, the molecular mechanisms linking gangliosides variation with APP expression are still unknown. In this study, we used APP isoforms 770, 751, and 695 stable lines and knockdown APP by siRNA to examine the cell surface ganglioside alteration. Furthermore, APP is cleaved to produce Aβ and the APP intracellular domain (AICD) by β and γ-secretase. The result of ganglioside change may be associated with AICD-meditated effect, not Aβ monomer.
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author2 |
Yun-Ru Chen |
author_facet |
Yun-Ru Chen Tien-Wei Lin 林天偉 |
author |
Tien-Wei Lin 林天偉 |
spellingShingle |
Tien-Wei Lin 林天偉 Understanding amyloid-beta and amyloid precursor protein in Alzheimer’s disease with characterization of Amyloid-β A2 Variant effect and cell surface gangliosides |
author_sort |
Tien-Wei Lin |
title |
Understanding amyloid-beta and amyloid precursor protein in Alzheimer’s disease with characterization of Amyloid-β A2 Variant effect and cell surface gangliosides |
title_short |
Understanding amyloid-beta and amyloid precursor protein in Alzheimer’s disease with characterization of Amyloid-β A2 Variant effect and cell surface gangliosides |
title_full |
Understanding amyloid-beta and amyloid precursor protein in Alzheimer’s disease with characterization of Amyloid-β A2 Variant effect and cell surface gangliosides |
title_fullStr |
Understanding amyloid-beta and amyloid precursor protein in Alzheimer’s disease with characterization of Amyloid-β A2 Variant effect and cell surface gangliosides |
title_full_unstemmed |
Understanding amyloid-beta and amyloid precursor protein in Alzheimer’s disease with characterization of Amyloid-β A2 Variant effect and cell surface gangliosides |
title_sort |
understanding amyloid-beta and amyloid precursor protein in alzheimer’s disease with characterization of amyloid-β a2 variant effect and cell surface gangliosides |
publishDate |
2017 |
url |
http://ndltd.ncl.edu.tw/handle/34549949595275845760 |
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