| Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric a{beta}. | |
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MedLine Citation:
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PMID: 19406747 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Accumulation of amyloid beta (Abeta) oligomers in the brain is toxic to synapses and may play an important role in memory loss in Alzheimer disease. However, how these toxins are built up in the brain is not understood. In this study we investigate whether impairments of insulin and insulin-like growth factor-1 (IGF-1) receptors play a role in aggregation of Abeta. Using primary neuronal culture and immortal cell line models, we show that expression of normal insulin or IGF-1 receptors confers cells with abilities to reduce exogenously applied Abeta oligomers (also known as ADDLs) to monomers. In contrast, transfection of malfunctioning human insulin receptor mutants, identified originally from patient with insulin resistance syndrome, or inhibition of insulin and IGF-1 receptors via pharmacological reagents increases ADDL levels by exacerbating their aggregation. In healthy cells, activation of insulin and IGF-1 receptor reduces the extracellular ADDLs applied to cells via seemingly the insulin-degrading enzyme activity. Although insulin triggers ADDL internalization, IGF-1 appears to keep ADDLs on the cell surface. Nevertheless, both insulin and IGF-1 reduce ADDL binding, protect synapses from ADDL synaptotoxic effects, and prevent the ADDL-induced surface insulin receptor loss. Our results suggest that dysfunctions of brain insulin and IGF-1 receptors contribute to Abeta aggregation and subsequent synaptic loss. |
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Authors:
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Wei-Qin Zhao; Pascale N Lacor; Hui Chen; Mary P Lambert; Michael J Quon; Grant A Krafft; William L Klein |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't Date: 2009-04-30 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 284 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-07-06 Completed Date: 2009-09-01 Revised Date: 2010-09-27 |
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: 18742-53 Citation Subset: IM |
Affiliation:
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Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA. wei-qin_zhao@merck.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amyloid beta-Protein
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chemistry*,
metabolism Animals Antigens, CD / chemistry* Brain / metabolism Humans Insulin / chemistry*, metabolism Insulin Resistance Insulin-Like Growth Factor I / metabolism Mice Models, Biological Mutation NIH 3T3 Cells Neurons / metabolism Neurotoxins / chemistry Rats Receptor, Insulin / chemistry* Synapses / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01-AG022547/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Protein; 0/Antigens, CD; 0/Neurotoxins; 11061-68-0/Insulin; 67763-96-6/Insulin-Like Growth Factor I; EC 2.7.10.1/INSR protein, human; EC 2.7.10.1/Receptor, Insulin |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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