2012 Fiscal Year Final Research Report
Development of apomorphine therapy for Alzheimer disease
| Project/Area Number |
22590936
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
MOTOMURA Kyoko (IINUMA Kyoko) 九州大学, 大学院・医学研究院, 技術職員 (20380644)
SAKAE Nobutaka 九州大学, 大学病院, 助教 (80423523)
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| Co-Investigator(Renkei-kenkyūsha) |
NAKABEPPU Yusaku 九州大学, 生体防御医学研究所, 教授 (30180350)
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| Project Period (FY) |
2010 – 2012
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| Keywords | 神経分子病態学 |
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| Research Abstract |
Alzheimer’s disease (AD) is the most frequent dementia in the elderly. However, the currently approved drugs’ effects on cognitive function are only slight, and novel drugs that improve memory function and inhibit neurodegeneration are being developed. We have found apomorphine (APO) to be a novel drug that targets amyloid-β42 (Aβ42) accumulating early in the neurons. In the present research theme, using cultured cells, AD mouse model (3xTg-AD) and brain tissues of AD patients, we have demonstrated
1) that the majority of Aβ42 accumulating in the neurons is the Aβ42 oligomer with toxic turn formation;
2) that accumulation of the toxic turn Aβ42 oligomer is associated wuth endoplasmic reticulum stress;
3) that APO treatment promotes degradation of the toxic turn Aβ42 oligomer;
4) APO treatment is more effective for the AD mouse model than lithium treatment which inhibits hyper-phosphrylation of tau protein;
5) that Apokyn（R）, a drug of APO for Parkinson’s disease patients, is effective enough at low dose for memory function of the AD mouse model;
6) that the anti-AD effects of APO is not simply due to stimulation of dopamine receptors;
7) that APO elevates the activity of Insulin-degrading enzyme (IDE) in the cultured cells; and
8) that one of the molecular mechanisms of APO effects may be inhibition of the insulin resistance leading to elevation of the IDE activity.
In the future, we will study about elevation of the insulin resistance in the brains of the AD mouse model and effects of APO treatment on the insulin resistance, and develop new drugs for the brain diabetes in AD.
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[Journal Article] Intracellular accumulation of toxic turn amyloid-β is associated with endoplasmic reticulum stress in Alzheimer's disease.2013
Author(s)
Soejima N, Ohyagi Y, Nakamura N, Himeno E, Iinuma KM, Sakae N, Yamasaki R, Tabira T, Murakami K, Irie K, Kinoshita N, LaFerla FM, Kiyohara Y, Iwaki T, Kira J
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Journal Title
CurrAlzheimer Res
Volume: 10
Pages: 11-20
DOI
Peer Reviewed
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[Journal Article] Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation.2011
Author(s)
Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi K, Sakae N, Motomura K, Soejima N, Yamasaki R, Hashimoto T, Tabira T, LaFerla FM, Kira J
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Journal Title
Ann Neurol
Volume: 69
Pages: 248-256
DOI
Peer Reviewed
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[Journal Article] Activation of glutathione peroxidase and inhibition of p53-related apoptosis by apomorphine.2011
Author(s)
Ma L, Ohyagi Y, Nakamura N, Iinuma KM, Miyoshi K, Himeno E, Soejima N, Yanagihara YT, Sakae N, Yamasaki R, Kira J
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Journal Title
J Alzheimers Dis
Volume: 27
Pages: 225-237
DOI
Peer Reviewed
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