RGD Reference Report - An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease-associated Abeta oligomers. - Rat Genome Database

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An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease-associated Abeta oligomers.

Authors: Bomfim, TR  Forny-Germano, L  Sathler, LB  Brito-Moreira, J  Houzel, JC  Decker, H  Silverman, MA  Kazi, H  Melo, HM  McClean, PL  Holscher, C  Arnold, SE  Talbot, K  Klein, WL  Munoz, DP  Ferreira, ST  De Felice, FG 
Citation: Bomfim TR, etal., J Clin Invest. 2012 Mar 22. pii: 57256. doi: 10.1172/JCI57256.
RGD ID: 6482861
Pubmed: PMID:22476196   (View Abstract at PubMed)
PMCID: PMC3314445   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI57256   (Journal Full-text)

Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-beta peptide (Abeta) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-alpha pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Abeta oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease  ISOIrs1 (Mus musculus)6482861; 6482861protein:increased serine phosphorylation:hippocampusRGD 
Alzheimer's disease  IDA 6482861protein:increased serine phosphorylation:hippocampusRGD 

Objects Annotated

Genes (Rattus norvegicus)
Irs1  (insulin receptor substrate 1)

Genes (Mus musculus)
Irs1  (insulin receptor substrate 1)

Genes (Homo sapiens)
IRS1  (insulin receptor substrate 1)


Additional Information