Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 122, Issue 4, Pages 1339-1353Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI57256
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Funding
- Human Frontier Science Program (HFSP)
- John Simon Guggenheim Memorial Foundation
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
- Instituto Nacional de Neurociencia Translacional (INNT)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico and Coordenacao de Aperfeicoamento de Pessoal de Ensino Superior
- Canadian Institutes of Health Research [MOP-77734, 90396]
- HFSP
- Canada Research Chair
- American Health Assistance Foundation
- Alzheimer's Association
- NIH-National Institute on Aging [R01-AG18877, R01-AG22547]
- Temple Foundation
- National Science and Engineering Research Council [327100-06]
- Canadian Foundation for Innovation [12793]
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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-beta peptide (A beta) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-alpha pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocarnpal 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 A beta 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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