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Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline.

Authors: Talbot, K  Wang, HY  Kazi, H  Han, LY  Bakshi, KP  Stucky, A  Fuino, RL  Kawaguchi, KR  Samoyedny, AJ  Wilson, RS  Arvanitakis, Z  Schneider, JA  Wolf, BA  Bennett, DA  Trojanowski, JQ  Arnold, SE 
Citation: Talbot K, etal., J Clin Invest. 2012 Mar 22. pii: 59903. doi: 10.1172/JCI59903.
Pubmed: (View Article at PubMed) PMID:22476197
DOI: Full-text: DOI:10.1172/JCI59903

While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR-->IRS-1-->PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R-->IRS-2-->PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS616) and IRS-1 pS636/639. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE epsilon4 status. Levels of IRS-1 pS616 and IRS-1 pS636/639 and their activated kinases correlated positively with those of oligomeric Abeta plaques and were negatively associated with episodic and working memory, even after adjusting for Abeta plaques, neurofibrillary tangles, and APOE epsilon4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Abeta oligomers and yet promoting cognitive decline independent of classic AD pathology.

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RGD Object Information
RGD ID: 6482860
Created: 2012-05-08
Species: All species
Last Modified: 2012-05-08
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.