An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers
Theresa R. Bomfim, Leticia Forny-Germano, Luciana B. Sathler, Jordano Brito-Moreira, Jean-Christophe Houzel, Helena Decker, Michael A. Silverman, Hala Kazi, Helen M. Melo, Paula L. McClean, Christian Holscher, Steven E. Arnold, Konrad Talbot, William L. Klein, Douglas P. Munoz, Sergio T. Ferreira, Fernanda G. De Felice
Theresa R. Bomfim, Leticia Forny-Germano, Luciana B. Sathler, Jordano Brito-Moreira, Jean-Christophe Houzel, Helena Decker, Michael A. Silverman, Hala Kazi, Helen M. Melo, Paula L. McClean, Christian Holscher, Steven E. Arnold, Konrad Talbot, William L. Klein, Douglas P. Munoz, Sergio T. Ferreira, Fernanda G. De Felice
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Research Article

An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers

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

Theresa R. Bomfim, Leticia Forny-Germano, Luciana B. Sathler, Jordano Brito-Moreira, Jean-Christophe Houzel, Helena Decker, Michael A. Silverman, Hala Kazi, Helen M. Melo, Paula L. McClean, Christian Holscher, Steven E. Arnold, Konrad Talbot, William L. Klein, Douglas P. Munoz, Sergio T. Ferreira, Fernanda G. De Felice

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Figure 5

Elevated p-JNK levels in AD brains and in hippocampi of cynomolgus monkeys that received i.c.v. injections of AβOs.

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Elevated p-JNK levels in AD brains and in hippocampi of cynomolgus monke...
(A–D) Density of neurons in the same segment of hippocampal field CA1 with detectable JNK1/2pT183/pY185 in NCI controls (A) or AD patients (B). In control cases (A), immunoreactivity for p-JNK is generally limited to portions of cell nuclei (arrow), with only a small number of neurons showing immunoreactivity in the cytoplasm (arrowheads). Neurons with detectable cytoplasmic JNK1/2 pT183/pY185 also showed increased levels of this activated protein in AD (B and C) as indicated by higher mean OD in AD than in control samples (D). Graphs show mean values ± SD for neurons throughout CA1 in 22 matched pairs of control and AD cases. *P < 0.0001 relative to NCI individuals. (E–H) p-JNK immunoreactivities in the same segments of the dentate gyri from a sham-operated monkey (E) and 3 different monkeys that received i.c.v. injections of AβOs (F–H). (I) p-JNK immunolabeling density determined (see Methods) from 20–33 images acquired from dentate gyri of sham (S) or oligomer-injected monkeys (M1–M3). *P < 0.001 relative to the sham-operated monkey, ANOVA followed by Bonferroni post-hoc test. J, K, and L, enlarged images demonstrating both cytoplasmic and nuclear p-JNK labeling (J) of NeuN-positive cells (K). (L) p-JNK immunoreactivity was not associated with GFAP-positive cells. Scale bars: 50 μm (A, B, and E–H); 5 μm (J–L).