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An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers.
J Clin Invest 2012; 122(4):1339-53JCI

Abstract

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.

Authors+Show Affiliations

Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

Language

eng

PubMed ID

22476196

Citation

Bomfim, Theresa R., et al. "An Anti-diabetes Agent Protects the Mouse Brain From Defective Insulin Signaling Caused By Alzheimer's Disease- Associated Aβ Oligomers." The Journal of Clinical Investigation, vol. 122, no. 4, 2012, pp. 1339-53.
Bomfim TR, Forny-Germano L, Sathler LB, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers. J Clin Invest. 2012;122(4):1339-53.
Bomfim, T. R., Forny-Germano, L., Sathler, L. B., Brito-Moreira, J., Houzel, J. C., Decker, H., ... De Felice, F. G. (2012). An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers. The Journal of Clinical Investigation, 122(4), pp. 1339-53. doi:10.1172/JCI57256.
Bomfim TR, et al. An Anti-diabetes Agent Protects the Mouse Brain From Defective Insulin Signaling Caused By Alzheimer's Disease- Associated Aβ Oligomers. J Clin Invest. 2012;122(4):1339-53. PubMed PMID: 22476196.
* Article titles in AMA citation format should be in sentence-case
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 - 2011/01/26/received PY - 2012/01/05/accepted PY - 2012/4/6/entrez PY - 2012/4/6/pubmed PY - 2012/7/7/medline SP - 1339 EP - 53 JF - The Journal of clinical investigation JO - J. Clin. Invest. VL - 122 IS - 4 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. SN - 1558-8238 UR - https://www.unboundmedicine.com/medline/citation/22476196/An_anti_diabetes_agent_protects_the_mouse_brain_from_defective_insulin_signaling_caused_by_Alzheimer's_disease__associated_Aβ_oligomers_ L2 - https://doi.org/10.1172/JCI57256 DB - PRIME DP - Unbound Medicine ER -