Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers
AU - Bomfim, Theresa R.
AU - Forny-Germano, Leticia
AU - Sathler, Luciana B.
AU - Brito-Moreira, Jordano
AU - Houzel, Jean-Christophe
AU - Decker, Helena
AU - Silverman, Michael A.
AU - Kazi, Hala
AU - Melo, Helen M.
AU - McClean, Paula L.
AU - Holscher, Christian
AU - Arnold, Steven E.
AU - Talbot, Konrad
AU - Klein, William L.
AU - Munoz, Douglas P.
AU - Ferreira, Sergio T.
AU - De Felice, Fernanda G.
PY - 2012/4/2
Y1 - 2012/4/2
N2 - 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 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 Aβ 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.
AB - 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 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 Aβ 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.
KW - Aged
KW - Aged, 80 and over
KW - Alzheimer Disease
KW - Amyloid beta-Peptides
KW - Animals
KW - Antibodies, Monoclonal
KW - Cells, Cultured
KW - Female
KW - Hippocampus
KW - Humans
KW - Hypoglycemic Agents
KW - Insulin
KW - Insulin Receptor Substrate Proteins
KW - Insulin Resistance
KW - MAP Kinase Signaling System
KW - Macaca fascicularis
KW - Male
KW - Maze Learning
KW - Memory Disorders
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Middle Aged
KW - Neurons
KW - Peptides
KW - Phosphorylation
KW - Protein Processing, Post-Translational
KW - Rats
KW - Venoms
U2 - 10.1172/JCI57256
DO - 10.1172/JCI57256
M3 - Journal article
C2 - 22476196
VL - 122
SP - 1339
EP - 1353
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 1558-8238
IS - 4
ER -