2011 Fiscal Year Final Research Report
Clarification of the molecular mechanism underlying the neuronal death induced by ACE inhibition in APP transgenic mouse
| Project/Area Number |
22700399
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | Iwate Medical University |
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Principal Investigator |
ZOU Kun 岩手医科大学, 薬学部, 助教 (40450837)
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| Co-Investigator(Renkei-kenkyūsha) |
KOMANO Hiroto 岩手医科大学, 薬学部神経科学講座, 教授 (40170378)
MICHIKAWA Makoto 国立長寿医療センター研究所, アルツハイマー病研究部, 部長 (40270912)
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| Project Period (FY) |
2010 – 2011
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| Keywords | 精神・神経疾患の病態と治療 / アルツハイマー病 / アミロイドベータ蛋白 |
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| Research Abstract |
Amyloidβ-protein 1-42(Aβ42), as well as the elevation of the ratio of Aβ42 to the shorter major form of Aβ40, has been identified as important in early events in the pathogenesis of Alzheimer's disease. We have reported that Aβ40 has neuroprotective effects against metal-induced oxidative damage and Aβ42-induced neuronal death. We then identified angiotensin-converting enzyme(ACE) as an Aβ42-to-Aβ40-converting enzyme and found that ACE inhibition enhances Aβ42 deposition. ACE is one of the most commonly targeted enzymes by inhibitors in elderly hypertensive populations. To investigate whether ACE inhibition leads to neurodegeneration in the brain of Alzheimer's disease mouse model, we performed a long-term treatment of Tg2576 mice with a high or a low dose of ACE inhibitor. The treatment with high dose ACE inhibitor significantly reduced blood pressure and resulted in a lower survival rate of mice compared with the control and the low-dose treatment. In addition to the increase of Aβ42 deposition, other Alzheimer-like pathologies were also found in the brain of the high-dose ACE inhibitor treatment group, such as a thinner cerebral cortex, an enlarged lateral ventricle and enhanced tau phosphorylation. These results suggest that potent inhibition of ACE may be a risk factor for the development of Alzheimer's disease.
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