2019 Fiscal Year Final Research Report
Early Alzheimer-like pathogenic events in endocytic membrane traffic in Down Syndrome iPSC-derived neurons
| Project/Area Number |
16H04667
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Juntendo University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
貫名 信行 同志社大学, 脳科学研究科, 教授 (10134595)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Keywords | 脳神経疾患 / 認知症 |
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| Outline of Final Research Achievements |
Endosomal traffic dysfunction in neurons is known as the earliest pathogenic event both in Alzheimer’s disease and Down syndrome. Recent evidence suggests that one of the amyloid-β precursor protein metabolites, beta-carboxyl-terminus fragment (βCTF), accumulates in endosomes and would be responsible for the impairment of endocytic trafficking, but the mechanistic details remain unclear. We identified TMEM30a, a subcomponent of lipid flippase that translocates phospholipids from the outer to inner leaflet of the lipid bilayer, as a candidate partner for βCTF toxicity. TMEM30a interacts with βCTF in endosomes, and this complex impaired retrograde trafficking, leading to abnormally enlarged endosomes. We tried to demonstrate that the complex formation between TMEM30a and βCTF would be involved in the endosomal traffic dysfunction in Down syndrome iPSC-derived neurons and an organotypic hippocampal slice culture model of Alzheimer’s disease.
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| Free Research Field |
神経薬理学
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| Academic Significance and Societal Importance of the Research Achievements |
アルツハイマー病においては、細胞外のアミロイドβの産生過剰、分解・排出低下を背景とした凝集体形成が、細胞内のタウ凝集促進・伝搬、神経細胞死を惹起すると考えられている。しかし、大多数を占める孤発例においては、初期病変のエンドソーム障害がどのように凝集体形成につながるか明らかではない。また、アミロイド仮説にもとづく疾患修飾薬が期待されているが、アミロイド病理は発症の20年程前から始まっており、早期介入や効果判定のためのバイオマーカーが求められている。現在解明されていない初期病態の進展メカニズムを明らかにすることは、今後の予防、早期介入のために重要な知見となることが期待される。
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