An 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…

• AA
  Alzheimer's Association
• AH
  American Health Assistance Foundation
• JS
  John Simon Guggenheim Memorial Foundation
• TT
  T.L.L Temple Foundation
• CN
  Conselho Nacional de Desenvolvimento Científico e Tecnológico
• FC
  Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
• IN
  Instituto Nacional de Ciência e Tecnologia de Neurociência Translacional
• UF
  Universidade Federal do Rio de Janeiro
• NI
  National Institutes of Health

  Award: AG22547
• CI
  Canadian Institutes of Health Research

  Awards: 90396, MOP-77734