The Effect of a Novel Mutation on Amyloid Precursor Protein Processing
| Autor: | Ya-Tzu Lin, 林雅梓 |
|---|---|
| Rok vydání: | 2010 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 98 The deposition of amyloid beta peptide (Abeta), which is generated from amyloid precursor protein (APP) through sequential cleavage of alpha- and beta-secretases, is the pathological hallmark of Alzheimer’s disease (AD). Several different mutations at APP gene cause familial form of early-onset AD via different mechanisms. Recently, our collaborators found a novel APP mutation that is located within Abeta domain. We named this aspartate (D) to histidine (H) substitution as Taiwan mutation (APPD678H, APPTw). A Japanese group reported a Tottori-Japanese mutation at the same amino acid but with an asparagine (N) substitution (APPD678N, APPtot). This Tottori mutation does not affect Abeta production, but accelerates Abeta aggregation. The aim of this thesis is to investigate the potential mechanisms of this Taiwan mutation leading to the early-onset of AD development. We hypothesized that the Taiwan mutation may alter APP cleavage pattern to increase Abeta production. We generated expressing constructs carrying wild type or different mutant APP cDNA, and overexpressed them in HEK293 cells. APP metabolic products were determined by Western blot and enzyme-linked immunosorbent assay (ELISA). We found that the Taiwan mutation enhanced the production of Abeta42, beta-secretase cleaved APP C-terminal fragments and Abeta42/40 ratio. The alternation of APP processing may due to the higher ratio of APP retaining inside the cell. In conclusion, our results suggested that the Taiwan mutation may alter APP processing by secretases. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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