| Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function. | |
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MedLine Citation:
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PMID: 16636059 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A subtle but chronic alteration in metabolic balance between amyloid-beta peptide (Abeta) anabolic and catabolic activities is thought to cause Abeta accumulation, leading to a decade-long pathological cascade of Alzheimer disease. However, it is still unclear whether a reduction of the catabolic activity of Abeta in the brain causes neuronal dysfunction in vivo. In the present study, to clarify a possible connection between a reduction in neprilysin activity and impairment of synaptic and cognitive functions, we cross-bred amyloid precursor protein (APP) transgenic mice (APP23) with neprilysin-deficient mice and biochemically and immunoelectron-microscopically analyzed Abeta accumulation in the brain. We also examined hippocampal synaptic plasticity using an in vivo recording technique and cognitive function using a battery of learning and memory behavior tests, including Y-maze, novel-object recognition, Morris water maze, and contextual fear conditioning tests at the age of 13-16 weeks. We present direct experimental evidence that reduced activity of neprilysin, the major Abeta-degrading enzyme, in the brain elevates oligomeric forms of Abeta at the synapses and leads to impaired hippocampal synaptic plasticity and cognitive function before the appearance of amyloid plaque load. Thus, reduced neprilysin activity appears to be a causative event that is at least partly responsible for the memory-associated symptoms of Alzheimer disease. This supports the idea that a strategy to reduce Abeta oligomers in the brain by up-regulating neprilysin activity would contribute to alleviation of these symptoms. |
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Authors:
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Shu-Ming Huang; Akihiro Mouri; Hideko Kokubo; Ryuichi Nakajima; Takahiro Suemoto; Makoto Higuchi; Matthias Staufenbiel; Yukihiro Noda; Haruyasu Yamaguchi; Toshitaka Nabeshima; Takaomi C Saido; Nobuhisa Iwata |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2006-04-24 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 281 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2006 Jun |
Date Detail:
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Created Date: 2006-06-26 Completed Date: 2006-08-18 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 17941-51 Citation Subset: IM |
Affiliation:
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Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alzheimer Disease
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metabolism,
pathology,
physiopathology* Amyloid beta-Protein / genetics, metabolism* Animals Cognition / physiology* Female Hippocampus / metabolism, pathology, physiopathology Male Maze Learning / physiology Memory / physiology Mice Mice, Transgenic Microscopy, Electron Neprilysin / genetics, metabolism* Neuronal Plasticity / physiology* Peptide Fragments / metabolism Synapses / pathology, physiology, ultrastructure |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Protein; 0/Peptide Fragments; EC 3.4.24.11/Neprilysin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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