2007 Fiscal Year Final Research Report Summary
Molecular mechanisms of mitochondrial dysfunction and neurotoxicity induced by Aβ-ARAD interaction
| Project/Area Number |
18590050
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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 |
Biological pharmacy
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| Research Institution | Kanazawa University |
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Principal Investigator |
TAKUMA Kazuhiro Kanazawa University, Graduate School of Natural Science and Technology, Associate Professor (90289025)
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| Co-Investigator(Kenkyū-buntansha) |
YAMADA Kiyofumi Nagoya University, Graduate School of Medicine, Professor (30303639)
NAGAI Taku Nagoya University, Graduate School of Medicine, Assistant Professor (10377426)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Alzheimer's disease / neuron cultures / β-amyloid / ABAD / RAGE / mitochondria / apoptosis |
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| Research Abstract |
Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by senile plaques, neurofibrillary tangles, and neuronal loss A pathological hallmark of AD is the deposition of amyloid β-peptide (Aβ), a 39-43-amino acid peptides derived from the transmembrane amyloid precursor protein (APP).The fibrillar Aβ deposits a found in the extracellular senile plaque cores and associated with neurogedeneration in AD. In contrast, recent studies suggest that the accumulation of intraneuronal Aβ may be an early event in the pathogenesis of AD. However, the mechanisms of the neuronal membrane Pp transport system are unknown while Aβ is predominantly produced at the plasma membrane and released into the extracellular spaces. In this study, we demonstrate that receptor for advanced glycation endproducts (RAGE) contributes to transport of Aβ from the cell surface to the intracellular space. Mouse cortical neurons exposed to extracellular human Aβ(1-40) and Aβ_(1-42) subsequently showed detectable peptide intracellularly in the cytosol and mitochondria Pretreatment of cultured neurons from wild-type mice with neutralizing antibody to RAGE and neurons from RAGE null mice displayed decreased Aβ uptake and Aβ-mediated mitochondrial dysfunction. Aβ activated p38 MARK but not ERK1/2 and SARK/JNK, and then stimulated intracellular uptake of Aβ. Immunoblotting with anti-RAGE IgG demonstrated >8-fold more RAGE antigen had been immunoprecipitated from cells exposed to Aft compared with non-treated control Similar intraneuronal co-localization of Aβ and RAGE was observed in the hippocampus of transgenic mice overexpressing mutant APP. These findings indicate that RAGE-dependent activation of p38 MAPK pathway contributes to mechanisms involved in the translocation of Aβ from the extracellular to the intracellular space, thereby enhancing Aβ cytotoxicity.
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[Presentation] Neuronal uptake of amyloid β-peptide and its cellular toxicity2006
Author(s)
Emiko, Fukuzaki
Organizer
The Joint Meeting of the 28th Annual Meeting of the Japanese Society of Biological Psychiatry, the 36th Annual Meeting of the Japanese Society of Neuropsychopharmacology, and the 49th Annual Meeting of the Japanese Society of Neurochemistry
Place of Presentation
Nagoya
Year and Date
2006-09-14
Description
「研究成果報告書概要(欧文)」より
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