2018 Fiscal Year Final Research Report
Analuses of mitochondrial dysfunction depending on the species of pathogenic molecules in Alzheimer's disease
| Project/Area Number |
16K09664
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | University of Tsukuba |
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Principal Investigator |
Tamaoka Akira 筑波大学, 医学医療系, 教授 (50192183)
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| Co-Investigator(Kenkyū-buntansha) |
冨所 康志 筑波大学, 医学医療系, 講師 (80447250)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | Alzheimer's disease / mitochondria / amyloid β protein / amyloid precursor / oxidative stress / autophagy / lysosome / transcription factor EB |
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| Outline of Final Research Achievements |
We investigated whether Amyloid β-protein (Aβ) is generated locally from amyloid precursor protein (APP) within mitochondria by analyzing the expression patterns of APP and related molecules in mitochondria separated from human neuroblastoma SH-SY5Y cells and those expressing Swedish mutant APP. In view of the particularly low expression levels of BACE1, γ-secretase complex proteins, and β-CTF in mitochondria, we propose that it is unlikely that Aβ generation from APP occurs locally within this organelle. On the other hand, abnormalities of the autophagy-lysosomal pathway (ALP) have been implicated in the pathology of AD. Activation of TFEB (transcription factor EB), a master regulator of the ALP, leads to ALP facilitation. The present study sought to clarify whether TFEB-mediated ALP facilitation influences the process of Aβ generation in neurons, indicating that TFEB-mediated ALP enhancement appears to have dual, but opposite, effects on Aβ production in neurons.
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| Free Research Field |
神経内科学
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| Academic Significance and Societal Importance of the Research Achievements |
ADではAβのフリーラジカル化した毒性構造体が増加している事やAβオリゴマーがミトコンドリア障害性に作用する事が示されて来た。本研究では、AD発症における病因関連分子であるAβがAD発症を促進する機序に関して、特にミトコンドリアとの関係を中心に解析した。SH-SY5Y細胞を用いた実験により、APPよりのAβの産生は、ミトコンドリアにおいては生じていないものと考えられた。また、APPの細胞内代謝を解析では、TFEBによるALP促進がAβ分泌量に与える影響は、主にβ-CTFレベルの変化によるものと考えられた。今後は、酸化ストレスやミトコンドリア障害とALPやTFEBとの関係を解析する必要がある。
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