Cited by 1,871Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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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

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Talbot, Konrad, Wang, Hoau-Yan, Kazi, Hala, Han, Li-Ying, Bakshi, Kalindi P., Stucky, Andres, Fuino, Robert L., Kawaguchi, Krista R., Samoyedny, Andrew J., Wilson, Robert S., Arvanitakis, Zoe, Schneider, Julie A., Wolf, Bryan A., Bennett, David A., Trojanowski, John Q., Arnold, Steven E.·2012·Journal of Clinical Investigation

DOI 10.1172/jci59903PMC PMC3314463

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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.

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Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ
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Akt Mediates the Cross-Talk Between β-Adrenergic and Insulin Receptors in Neonatal Cardiomyocytes
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HIGH‐AFFINITY TRANSPORT AND PHOSPHORYLATION OF 2‐DEOXY‐ d ‐GLUCOSE IN SYNAPTOSOMES1,2
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The insulin‐regulated aminopeptidase IRAP is colocalised with GLUT4 in the mouse hippocampus – potential role in modulation of glucose uptake in neurones?
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Dissociating β-Amyloid from α7 Nicotinic Acetylcholine Receptor by a Novel Therapeutic Agent, S 24795, Normalizes α7 Nicotinic Acetylcholine and NMDA Receptor Function in Alzheimer's Disease Brain
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Incretin Analogues that have been Developed to Treat Type 2 Diabetes Hold Promise as a Novel Treatment Strategy for Alzheimers Disease
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Differential Roles of Insulin Receptor Substrates in the Anti-apoptotic Function of Insulin-like Growth Factor-1 and Insulin
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“Impaired neuronal insulin signaling reduces insulin-induced antiapoptosis (137, 138), promotes Aβ1–42–induced oxidative cell death (139), elevates Aβ1–42 secretion (120), blocks clearance of extracellular Aβ oligomers (117) as described above, and raises neuritic plaque loads (16, 19).”
Background
Exenatide prevents fat‐induced insulin resistance and raises adiponectin expression and plasma levels
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Muscle cell depolarization induces a gain in surface GLUT4 via reduced endocytosis independently of AMPK
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GLP-1 amplifies insulin signaling by up-regulation of IRβ, IRS-1 and Glut4 in 3T3-L1 adipocytes
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Immunolocalization of GLUTX1 in the Testis and to Specific Brain Areas and Vasopressin- Containing Neurons
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The Role of GLP-1 in Neuronal Activity and Neurodegeneration
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Expression of insulin-responsive glucose transporter GLUT4 mRNA in the rat brain and spinal cord: An in situ hybridization study
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Analysis of microdissected human neurons by a sensitive ELISA reveals a correlation between elevated intracellular concentrations of Aβ42 and Alzheimer’s disease neuropathology
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Insulin‐activated Akt rescues Aβ oxidative stress‐induced cell death by orchestrating molecular trafficking
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Glucose transporter GLUT8 translocation in neurons is not insulin responsive
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Chapter 13 Phosphorylation of IRS Proteins
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The Carboxyl Terminus of GLUT4 Contains a Serine-Leucine-Leucine Sequence That Functions as a Potent Internalization Motif in Chinese Hamster Ovary Cells
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Cerebellar Neurons Possess a Vesicular Compartment Structurally and Functionally Similar to Glut4-Storage Vesicles from Peripheral Insulin-Sensitive Tissues
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Insulin in Brain and Other Extrapancreatic Tissues of Vertebrates and Nonvertebrates
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Glucose transport in primary cultured neurons
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Dementia, Diabetes, Alzheimer's Disease, and Insulin Resistance in the Brain: Progress, Dilemmas, New Opportunities, and a Hypothesis to Tackle Intersecting Epidemics
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Chapter 12 Serine Kinases of Insulin Receptor Substrate Proteins
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Insulin receptors in the mammalian central nervous system: binding characteristics and subunit structure
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Differential Activation of Insulin Receptor Isoforms by Insulin-Like Growth Factors Is Determined by the C Domain
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Calcineurin mediates AKT dephosphorylation in the ischemic rat retina
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Insulin-like growth factor I (IGF-I) distribution in the tissue and extracellular compartment in different regions of rat brain
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Aβ1–42 stimulated T cells express P-PKC-δ and P-PKC-ζ in Alzheimer disease
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ELISA-Quantitation of Phosphorylated Tau Protein in the Alzheimer’s Disease Brain
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Short-term in vitro inhibition of glycogen synthase kinase 3 potentiates insulin signaling in type I skeletal muscle of Zucker Diabetic Fatty rats
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Reciprocal feedback regulation of insulin receptor and insulin receptor substrate tyrosine phosphorylation by phosphoinositide 3-kinase in primary adipocytes
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Insulin receptor mutation results in insulin resistance and hyperinsulinemia but does not exacerbate Alzheimer’s-like phenotypes in mice
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Pharmacological inhibition of GSK‐3 is not strictly correlated with a decrease in tyrosine phosphorylation of residues 216/279
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Dephosphorylation by Default, a Potential Mechanism for Regulation of Insulin Receptor Substrate-1/2, Akt, and ERK1/2
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Identification of Phosphorylation Sites in Insulin Receptor Substrate-1 by Hypothesis-Driven High-Performance Liquid Chromatography−Electrospray Ionization Tandem Mass Spectrometry
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Tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) by oxidant stress in cerebellar granule neurons: modulation by N-methyl-d-aspartate through calcineurin activity
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Power of pairwise comparisons in the equal variance and unequal sample size case
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Characterization of the glucose transporter from rat brain synaptosomes
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Authors: 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., Arvanitakis, Z., Schneider, J. A., Wolf, B. A., Bennett, D. A., Trojanowski, J. Q., & Arnold, S. E.
Affiliations: University of Pennsylvania (US)
City University of New York (US)
Rush University Medical Center (US)
Children's Hospital of Philadelphia (US)
Corresponding author: Talbot, Konrad
ORCID: Talbot, Konrad
Wang, Hoau-Yan
Arvanitakis, Zoe
Schneider, Julie A.
Bennett, David A.
Trojanowski, John Q.
Arnold, Steven E.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2012-04-02
Volume: 122
Issue: 4
Pages: 1316-1338
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci59903
PMC: PMC3314463
OpenAlex: W1982795519
Cited by: 1,871
References: 176
Citations by year: 2026: 118 · 2025: 147 · 2024: 120 · 2023: 114 · 2022: 157 · 2021: 168 · 2020: 175 · 2019: 145 · 2018: 146 · 2017: 109 · 2016: 116 · 2015: 125 · 2014: 111 · 2013: 93 · 2012: 26
FWCI: 75.52
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Alzheimer's Association (P30AG10161, R01 AG15819)
University of Pennsylvania
Rush University (R01 AG15819)
T.L.L Temple Foundation
National Institute on Aging (P30AG010124, R01AG015819, AG-10124, P30AG010161)
National Institute of General Medical Sciences (R25GM056833)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: Alzheimer's disease, brain insulin resistance, IGF-1 resistance, IRS-1, IRS-1 serine phosphorylation, insulin signaling, PI3K signaling, IGF-1 receptor, hippocampus, cerebellum, amyloid-beta oligomers, cognitive decline, episodic memory, working memory, APOE ε4, neurofibrillary tangles, mild cognitive impairment
MeSH terms: Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cerebellar Cortex, Cognition Disorders, Drug Resistance, Female, Glucose, Hippocampus, Humans, Insulin, Insulin Resistance, Insulin-Like Growth Factor I, Male, Middle Aged, Phosphorylation, Phosphoserine, Protein Processing, Post-Translational, Recombinant Proteins, Signal Transduction, Diabetes Complications, Apolipoprotein E4, Insulin Receptor Substrate Proteins

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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

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