論文名 | Mutation-induced loss of APP function causes GABAergic depletion in recessive familial Alzheimer's disease : analysis of Osaka mutation-knockin mice |
記事種別等 | Research |
著者名 | Umeda, Tomohiro / Kimura, Tetsuya / Yoshida, Kayo / Takao, Keizo / Fujita, Yuki / Matsuyama, Shogo / Sakai, Ayumi / Yamashita, Minato / Yamashita, Yuki / Ohnishi, Kiyouhisa / Suzuki, Mamiko / Takuma, Hiroshi / Miyakawa, Tsuyoshi / Takashima, Akihiko / Morita, Takashi / Mori, Hiroshi / Tomiyama, Takami |
著者名(別言語) | 梅田, 知宙 / 木村, 哲也 / 吉田, 佳世 / 高雄, 啓三 / 藤田, 有紀 / 松山, 正剛 / 酒井, 亜由美 / 山下, 港 / 山下, 優希 / 大西, 紀陽久 / 鈴木, 真美子 / 詫間, 浩 / 宮川, 剛 / 高島, 明彦 / 森田, 隆 / 森, 啓 / 富山, 貴美 |
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抄録・内容(英) | The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer's disease. While this mutation accelerates amyloid β (Aβ) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of Aβ oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than Aβ accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented Aβ oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of Aβ accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity. |
備考 | This study was supported by the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (no. 20023026, 21390271, 23110514, 25290018, 16K15132); by the Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by the Grants-in-Aid for Comprehensive Research on Dementia from the Ministry of Health, Labour, and Welfare, Japan; and in part by the Alzheimer's Association (IIRG-09-132,098). |
言語 | eng |
ページ開始 | 59 |
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著者版フラグ | publisher |
著者所属(英) | Osaka City University, Japan Science and Technology Agency / National Center for Geriatrics and Gerontology / Osaka City University / National Institute for Physiological Sciences / Osaka City University / Kobe University / Osaka City University / Osaka City University / Osaka City University / Osaka City University / National Center for Geriatrics and Gerontology / Osaka City University / National Institute for Physiological Sciences / National Center for Geriatrics and Gerontology / Osaka City University / Japan Science and Technology Agency, Osaka City University / Osaka City University, Japan Science and Technology Agency |
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刊行年月 | 2017-07-31 |
出版社 | BioMed Central |
ISSN | 2051-5960 |
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資料種別(英語) | Journal Article |
DOI | https://doi.org/10.1186/s40478-017-0461-5 |
CCライセンス(BY) | この作品はクリエイティブ・コモンズ 表示 4.0 国際 ライセンスの下に提供されています。 |
権利 | © The Author(s). 2017 |