Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline
Konrad Talbot, Hoau-Yan Wang, Hala Kazi, Li-Ying Han, Kalindi P. Bakshi, Andres Stucky, Robert L. Fuino, Krista R. Kawaguchi, Andrew J. Samoyedny, Robert S. Wilson, Zoe Arvanitakis, Julie A. Schneider, Bryan A. Wolf, David A. Bennett, John Q. Trojanowski, Steven E. Arnold
Konrad Talbot, Hoau-Yan Wang, Hala Kazi, Li-Ying Han, Kalindi P. Bakshi, Andres Stucky, Robert L. Fuino, Krista R. Kawaguchi, Andrew J. Samoyedny, Robert S. Wilson, Zoe Arvanitakis, Julie A. Schneider, Bryan A. Wolf, David A. Bennett, John Q. Trojanowski, Steven E. Arnold
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Research Article

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

Abstract

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 ε4 status. Levels of IRS-1 pS616 and IRS-1 pS636/639 and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. 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 Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.

Authors

Konrad Talbot, Hoau-Yan Wang, Hala Kazi, Li-Ying Han, Kalindi P. Bakshi, Andres Stucky, Robert L. Fuino, Krista R. Kawaguchi, Andrew J. Samoyedny, Robert S. Wilson, Zoe Arvanitakis, Julie A. Schneider, Bryan A. Wolf, David A. Bennett, John Q. Trojanowski, Steven E. Arnold

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Figure 1

Ex vivo stimulation is a valid method for studying insulin signaling in postmortem HF.

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Ex vivo stimulation is a valid method for studying insulin signaling in ...
(A) Representative dose-response tests in 1 of 5 N adult humans at 0–100 nM insulin in immunoblots of phosphorylated or bound antigens from immunoprecipitates of the indicated antigens. (B) Sample blots on the rat HF, showing that PMIs up to 16 hours (n = 4 per PMI) had no substantial effect on basal levels of IRβ or signaling evoked by 1 or 10 nM insulin. Effects of insulin on IGF-1 signaling were also tested on the same samples (Supplemental Figure 2). (C) PMI effects on IRβ pY and IGF-1Rβ pY relative to total receptor levels (mean ± SEM). 1 nM insulin activated IRβ (P = 0.0015), but not IGF-1Rβ (see blots). 10 nM insulin induced greater activation of IRβ (P = 0.0063) as well as IGF-1Rβ (P = 0.0009). (D) PMI effects on IRS-1 bound to IRβ and IGF-1Rβ relative to total receptor levels (mean ± SEM). 1 nM insulin induced IRβ binding (P = 0.0002), but not IGF-1Rβ binding (see blots), of IRS-1. 10 nM insulin induced greater IRβ binding (P = 0.0009) as well as IGF-1Rβ binding (P = 0.0007) of IRS-1. kDa values correspond to the molecular weight marker closest to the bands shown. *P < 0.005.