biostudies-literatureBomfim TRNIA NIH HHSCIHR1339-53https://www.ebi.ac.uk/biostudies/studies/S-EPMC3314445biostudies-literatureUnknown122(4)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-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in The Journal of clinical investigationAn anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers.PMC331444590396R01-AG22547R01 AG018877MOP-77734R01 AG022547R01-AG18877Klein WLBomfim TRSathler LBKazi HForny-Germano LMunoz DPMcClean PLBrito-Moreira JHouzel JCTalbot KDe Felice FGSilverman MAMelo HMArnold SEDecker HFerreira STHolscher CfalseAn anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers.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-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in 2012-01-01T00:00:00Z2012 Apr2025-04-05T15:41:59.346Z2019-03-27T00:51:40ZS-EPMC33144452247619610.1172/jci5725610.1172/JCI57256