Cited by 590Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Amyloid beta oligomers induce impairment of neuronal insulin receptors

Zhao, Wei‐Qin, De Felice, Fernanda G., Fernandez, Sara, Chen, Hui, Lambert, Mary P., Quon, Michael J., Krafft, Grant A., Klein, William L.·2008·The FASEB Journal

DOI 10.1096/fj.06-7703com

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Abstract

Recent studies have indicated an association between Alzheimer's disease (AD) and central nervous system (CNS) insulin resistance. However, the cellular mechanisms underlying the link between these two pathologies have not been elucidated. Here we show that signal transduction by neuronal insulin receptors (IR) is strikingly sensitive to disruption by soluble Abeta oligomers (also known as ADDLs). ADDLs are known to accumulate in AD brain and have recently been implicated as primary candidates for initiating deterioration of synapse function, composition, and structure. Using mature cultures of hippocampal neurons, a preferred model for studies of synaptic cell biology, we found that ADDLs caused a rapid and substantial loss of neuronal surface IRs specifically on dendrites bound by ADDLs. Removal of dendritic IRs was associated with increased receptor immunoreactivity in the cell body, indicating redistribution of the receptors. The neuronal response to insulin, measured by evoked IR tyrosine autophosphorylation, was greatly inhibited by ADDLs. Inhibition also was seen with added glutamate or potassium-induced depolarization. The effects on IR function were completely blocked by NMDA receptor antagonists, tetrodotoxin, and calcium chelator BAPTA-AM. Downstream from the IR, ADDLs induced a phosphorylation of Akt at serine473, a modification associated with neurodegenerative and insulin resistance diseases. These results identify novel factors that affect neuronal IR signaling and suggest that insulin resistance in AD brain is a response to ADDLs, which disrupt insulin signaling and may cause a brain-specific form of diabetes as part of an overall pathogenic impact on CNS synapses.

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Authors: Zhao, W., De Felice, F. G., Fernandez, S., Chen, H., Lambert, M. P., Quon, M. J., Krafft, G. A., & Klein, W. L.
Affiliations: Department of Neurobiology and Physiology Northwestern University Evanston Illinois USA
Northwestern University (US)
National Institutes of Health (US)
Blanchette Rockefeller Neurosciences Institute (US)
Acumen Pharmaceuticals (United States) (US)
ORCID: Quon, Michael J.
Klein, William L.
Venue: The FASEB Journal
Publisher: Wiley
Published: 2007-08-24
Volume: 22
Issue: 1
Pages: 246-260
ISSN: 0892-6638 (ISSN-L)
1530-6860
DOI: 10.1096/fj.06-7703com
OpenAlex: W2144486959
Semantic Scholar: 0a3dc4e52b02b85d3d180f43a62aee9078ca629b
Cited by: 587
References: 109
Citations by year: 2026: 13 · 2025: 21 · 2024: 21 · 2023: 22 · 2022: 37 · 2021: 34 · 2020: 28 · 2019: 29 · 2018: 38 · 2017: 42 · 2016: 51 · 2015: 46 · 2014: 35 · 2013: 30 · 2012: 39
FWCI: 14.69
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: The FASEB Journal (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute on Aging (RO1‐AG18877)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: amyloid-beta oligomers, Alzheimer's disease, insulin resistance, insulin signaling, tyrosine autophosphorylation, NMDA receptor, Akt phosphorylation, hippocampal neurons, synaptic dysfunction
MeSH terms: Animals, Biopolymers, Cells, Cultured, Dendrites, Humans, Insulin, Neurons, Phosphorylation, Protein-Tyrosine Kinases, Receptor, Insulin, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Amyloid beta-Peptides, Rats, Sprague-Dawley, Rats

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Amyloid beta oligomers induce impairment of neuronal insulin receptors

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