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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.
J Clin Invest 2012; 122(4):1316-38JCI

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+Show Affiliations

Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-3403, USA. talbotk2@mail.med.upenn.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22476197

Citation

Talbot, Konrad, et al. "Demonstrated Brain Insulin Resistance in Alzheimer's Disease Patients Is Associated With IGF-1 Resistance, IRS-1 Dysregulation, and Cognitive Decline." The Journal of Clinical Investigation, vol. 122, no. 4, 2012, pp. 1316-38.
Talbot K, Wang HY, Kazi H, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122(4):1316-38.
Talbot, K., Wang, H. Y., Kazi, H., Han, L. Y., Bakshi, K. P., Stucky, A., ... Arnold, S. E. (2012). Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. The Journal of Clinical Investigation, 122(4), pp. 1316-38. doi:10.1172/JCI59903.
Talbot K, et al. Demonstrated Brain Insulin Resistance in Alzheimer's Disease Patients Is Associated With IGF-1 Resistance, IRS-1 Dysregulation, and Cognitive Decline. J Clin Invest. 2012;122(4):1316-38. PubMed PMID: 22476197.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. AU - Talbot,Konrad, AU - Wang,Hoau-Yan, AU - Kazi,Hala, AU - Han,Li-Ying, AU - Bakshi,Kalindi P, AU - Stucky,Andres, AU - Fuino,Robert L, AU - Kawaguchi,Krista R, AU - Samoyedny,Andrew J, AU - Wilson,Robert S, AU - Arvanitakis,Zoe, AU - Schneider,Julie A, AU - Wolf,Bryan A, AU - Bennett,David A, AU - Trojanowski,John Q, AU - Arnold,Steven E, PY - 2012/4/6/entrez PY - 2012/4/6/pubmed PY - 2012/7/7/medline SP - 1316 EP - 38 JF - The Journal of clinical investigation JO - J. Clin. Invest. VL - 122 IS - 4 N2 - 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. SN - 1558-8238 UR - https://www.unboundmedicine.com/medline/citation/22476197/Demonstrated_brain_insulin_resistance_in_Alzheimer's_disease_patients_is_associated_with_IGF_1_resistance_IRS_1_dysregulation_and_cognitive_decline_ L2 - https://doi.org/10.1172/JCI59903 DB - PRIME DP - Unbound Medicine ER -