The DOI matches its Crossref record; 77 of the 77 references it cites were found in a registry or an index.
An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers
Open accessAbstract
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.
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1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
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Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins
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Self-citationA central role for JNK in obesity and insulin resistance
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Protection from obesity-induced insulin resistance in mice lacking TNF-α function
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Cited by
Talbot, K., Wang, H.-Y., Kazi, H., Han, L.-Y., Bakshi, K. P., Stucky, A., Fuino, R. L., Kawaguchi, K. R., Samoyedny, A. J., Wilson, R. S., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59903 · Cited by 1,871
Self-citationBrain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums
Arnold, S. E., Arvanitakis, Z., Macauley-Rambach, S. L., Koenig, A. M., Wang, H.-Y., Ahima, R. S., Craft, S., Gandy, S., Buettner, C., Stoeckel, L. E., et al. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.185 · Cited by 1,597
Self-citationPharmacology, physiology, and mechanisms of incretin hormone action.
Campbell, J. E., & Drucker, D. J. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.008 · Cited by 1,500
Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138
“331,341 Dysregulated neurotrophic signaling pathway Neurotrophic factors not only promote the survival, growth, and differentiation of neurons but are also crucial for maintaining synaptic plasticity and neuronal signaling functions.”
BackgroundExercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models
Lourenco, M. V., Frozza, R. L., de Freitas, G. B., Zhang, H., Kincheski, G. C., Ribeiro, F. C., Gonçalves, R. A., Clarke, J. R., Beckman, D., Staniszewski, A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0275-4 · Cited by 935
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Metadata
- Authors
- Bomfim, T. R., Forny-Germano, L., Sathler, L. B., Brito-Moreira, J., Houzel, J.-C., Decker, H., Silverman, M. A., Kazi, H., Melo, H. M., McClean, P. L., Holscher, C., Arnold, S. E., Talbot, K., Klein, W. L., Munoz, D. P., Ferreira, S. T., & De Felice, F. G.
- Venue
- Journal of Clinical Investigation
- Published
- 2012-04-02
- Volume
- 122
- Issue
- 4
- Pages
- 1339-1353
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2150472993
- Cited by
- 832
- References
- 77
- FWCI
- 34.15
- Type
- journal article
- Language
- en
- Open access
- green
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- Bomfim, T. R., Forny-Germano, L., Sathler, L. B., Brito-Moreira, J., Houzel, J.-C., Decker, H., Silverman, M. A., Kazi, H., Melo, H. M., McClean, P. L., Holscher, C., Arnold, S. E., Talbot, K., Klein, W. L., Munoz, D. P., Ferreira, S. T., & 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. Journal of Clinical Investigation. https://doi.org/10.1172/jci57256
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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