RGD Reference Report - Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling. - Rat Genome Database

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Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling.

Authors: Moloney, AM  Griffin, RJ  Timmons, S  O'Connor, R  Ravid, R  O'Neill, C 
Citation: Moloney AM, etal., Neurobiol Aging. 2010 Feb;31(2):224-43. doi: 10.1016/j.neurobiolaging.2008.04.002. Epub .
RGD ID: 10045894
Pubmed: PMID:18479783   (View Abstract at PubMed)
DOI: DOI:10.1016/j.neurobiolaging.2008.04.002   (Journal Full-text)

Insulin like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) signalling control vital growth, survival and metabolic functions in the brain. Here we describe specific and significant alterations in IGF-1R, IR, and their key substrate adaptor proteins IRS-1 and IRS-2 in Alzheimer's disease (AD). Western immunoblot analysis detected increased IGF-1R levels, and decreased levels of IGF-1-binding protein-2 (IGFBP-2), a major IGF-1-binding protein, in AD temporal cortex. Increased IGF-1R was observed surrounding and within amyloid-beta (Abeta)-containing plaques, also evident in an animal model of AD, and in astrocytes in AD. However, despite the overall increase in IGF-1R levels, a significantly lower number of neurons expressed IGF-1R in AD, and IGF-1R was aberrantly distributed in AD neurons especially evident in those with neurofibrillary tangles (NFTs). IR protein levels were similar in AD and control cases, however, the IR was concentrated intracellularly in AD neurons, unlike its distribution throughout the neuronal cell soma and in dendrites in control brain. Significant decreases in IRS-1 and IRS-2 levels were identified in AD neurons, in association with increased levels of inactivated phospho(Ser312)IRS-1 and phospho(Ser616)IRS-1, where increased levels of these phosphoserine epitopes colocalised strongly with NFTs. Our results show that IGF-1R and IR signalling is compromised in AD neurons and suggest that neurons that degenerate in AD may be resistant to IGF-1R/IR signalling.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease severityIEP 10045894protein:increased expression:temporal cortex:RGD 
Alzheimer's disease  ISOIgf1r (Mus musculus)10045894; 10045894protein:increased expression: cerebral cortex:RGD 
Alzheimer's disease  IEP 10045894protein:decreased expression:temporal cortex:RGD 
Alzheimer's disease  IEP 10045894protein:altered localization:brain and neuronRGD 
Alzheimer's disease severityIEP 10045894protein:altered expression:temporal cortex:RGD 
Alzheimer's disease severityIEP 10045894protein:decreased expression:temporal cortex:RGD 
Alzheimer's disease severityISOIGF1R (Homo sapiens)10045894; 10045894protein:increased expression:temporal cortex:RGD 
Alzheimer's disease  IEP 10045894protein:increased expression: cerebral cortex:RGD 
Alzheimer's disease  ISOIGFBP2 (Homo sapiens)10045894; 10045894protein:decreased expression:temporal cortex:RGD 
Alzheimer's disease  ISOINSR (Homo sapiens)10045894; 10045894protein:altered localization:brain and neuronRGD 
Alzheimer's disease severityISOIRS1 (Homo sapiens)10045894; 10045894protein:altered expression:temporal cortex:RGD 
Alzheimer's disease severityISOIRS2 (Homo sapiens)10045894; 10045894protein:decreased expression:temporal cortex:RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
neuronal cell body  IDA 10045894 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Igf1r  (insulin-like growth factor 1 receptor)
Igfbp2  (insulin-like growth factor binding protein 2)
Insr  (insulin receptor)
Irs1  (insulin receptor substrate 1)
Irs2  (insulin receptor substrate 2)

Genes (Mus musculus)
Igf1r  (insulin-like growth factor I receptor)
Igfbp2  (insulin-like growth factor binding protein 2)
Insr  (insulin receptor)
Irs1  (insulin receptor substrate 1)
Irs2  (insulin receptor substrate 2)

Genes (Homo sapiens)
IGF1R  (insulin like growth factor 1 receptor)
IGFBP2  (insulin like growth factor binding protein 2)
INSR  (insulin receptor)
IRS1  (insulin receptor substrate 1)
IRS2  (insulin receptor substrate 2)


Additional Information