| Brain insulin resistance accelerates Aß fibrillogenesis by inducing GM1 ganglioside clustering in the presynaptic membranes. | |
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MedLine Citation:
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PMID: 22260232 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Type 2 diabetes mellitus is thought to be a significant risk factor for Alzheimer's disease. Insulin resistance also affects the CNS by regulating key processes, such as neuronal survival and longevity, learning and memory. However, the mechanisms underlying these effects remain uncertain. To investigate whether insulin resistance is associated with the assembly of amyloid ß-protein at the cell surface of neurons, we inhibited insulin-signalling pathways of primary neurons. The treatments of insulin receptor (IR)-knockdown and a phosphatidylinositol 3-kinase inhibitor (LY294002), but not an extracellular signal-regulated kinase inhibitor, induced an increase in GM1 ganglioside levels in detergent-resistant membrane microdomains of the neurons. The aged db/db mouse brain exhibited reduction of IR expression and phosphorylation of Akt, which later induced an increase of the high-density GM1 ganglioside-clusters on synaptosomes. Neurons treated with IR knockdown or LY294002, and synaptosomes of the aged db/db mouse brains markedly accelerated an assembly of amyloid ß proteins. These results suggest that ageing and peripheral insulin resistance induce brain insulin resistance, which accelerate the assembly of amyloid ß proteins by increasing and clustering of GM1 gangliosides in detergent-resistant membrane microdomains of neuronal membranes. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry. |
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Authors:
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Naoki Yamamoto; Teruhiko Matsubara; Kazuya Sobue; Mamoru Tanida; Rika Kasahara; Kaori Naruse; Hideo Taniura; Toshinori Sato; Kenji Suzuki |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-19 |
Journal Detail:
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Title: Journal of neurochemistry Volume: - ISSN: 1471-4159 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985190R Medline TA: J Neurochem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry. |
Affiliation:
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Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan 525-8577 Department of Bioscience and Informatics, Keio University, Yokohama, Kanagawa, Japan 223-8522 Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan 467-8622 Laboratory of Applied Physiology, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan 525-8577 Laboratory of Molecular Medicinal Science, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan 525-8577. |
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