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 8

Exendin-4 prevents AβO-induced IRS-1pSer and p-JNK pathology and improves cognition in Tg mice.

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Exendin-4 prevents AβO-induced IRS-1pSer and p-JNK pathology and improve...
IRS-1pSer636 or IRS-1pTyr465 immunofluorescence of hippocampal neurons exposed for 3 hours to vehicle (A and E), 500 nM AβOs (B and F), 300 nM exendin-4 plus AβOs (C and G). Scale bar: 50 μm. Integrated IRS-1pSer636 (D) and IRS-1pTyr465 (H) immunofluorescence (4 independent experiments; 20 images analyzed/experimental condition/culture). *P < 0.001, relative to vehicle-treated cultures; #P < 0.001, relative to AβO-exposed cultures; **P < 0.001, relative to cultures treated with exendin-4 plus AβOs. (I and J) Total DCV (I) and mitochondria (Mito; J) transport in neurons exposed to 500 nM AβOs, 300 nM exendin-4 plus AβOs, or 1 μM insulin plus AβOs for 18 hours (15 neurons/condition from ≥2 cultures were analyzed). *P < 0.001 relative to vehicle-exposed cultures; #P < 0.001 relative to AβO-exposed cultures. (K and L) IRS-1pSer636, IRS-1pSer312, and p-JNK levels in hippocampi from 13-month-old WT mice (n = 5), vehicle-treated Tg mice (n = 7), or exendin-4–treated Tg mice (n = 5). Lanes were run on the same gel but were noncontiguous. Graphs show densitometric quantification of IRS-1pSer and p-JNK levels (normalized by total IRS-1 and JNK, respectively). *P < 0.05 relative to WT; #P < 0.001 relative to vehicle-treated Tg mice; ANOVA followed by Bonferroni post-hoc test. (M–O) Exendin-4 improves spatial memory. (M and N) and memory retention (O) in the Morris water maze (10-month-old vehicle- or exendin-4–treated Tg mice were used; n = 12 in both groups). (P and Q) Brain amyloid plaque load (scale bar: 50 μm) and soluble Aβ levels (R) in vehicle- or exendin-4–treated APP/PS1 mice (n = 6, both groups; *P < 0.05, Student’s t test).