RGD Reference Report - Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric a{beta}. - Rat Genome Database

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Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric a{beta}.

Authors: Zhao, Wei-Qin  Lacor, Pascale N  Chen, Hui  Lambert, Mary P  Quon, Michael J  Krafft, Grant A  Klein, William L 
Citation: Zhao WQ, etal., J Biol Chem. 2009 Jul 10;284(28):18742-53. doi: 10.1074/jbc.M109.011015. Epub 2009 Apr 30.
RGD ID: 13210538
Pubmed: PMID:19406747   (View Abstract at PubMed)
PMCID: PMC2707198   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M109.011015   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
InsrRatcell body located_inIDA PMID:19406747ARUK-UCL 
InsrRatdendrite located_inIDA PMID:19406747ARUK-UCL 
InsrRatneuronal cell body located_inIDA PMID:19406747ARUK-UCL 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
InsrRatcargo receptor activity enablesIMP PMID:19406747ARUK-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Ide  (insulin degrading enzyme)
Igf1r  (insulin-like growth factor 1 receptor)
Insr  (insulin receptor)
Mme  (membrane metallo-endopeptidase)


Additional Information