Cited by 154Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

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Zhao, Wei-Qin, Lacor, Pascale N., Chen, Hui, Lambert, Mary P., Quon, Michael J., Krafft, Grant A., Klein, William L.·2009·Journal of Biological Chemistry

Abstract

Accumulation of amyloid beta (Abeta) oligomers in the brain is toxic to synapses and may play an important role in memory loss in Alzheimer disease. However, how these toxins are built up in the brain is not understood. In this study we investigate whether impairments of insulin and insulin-like growth factor-1 (IGF-1) receptors play a role in aggregation of Abeta. Using primary neuronal culture and immortal cell line models, we show that expression of normal insulin or IGF-1 receptors confers cells with abilities to reduce exogenously applied Abeta oligomers (also known as ADDLs) to monomers. In contrast, transfection of malfunctioning human insulin receptor mutants, identified originally from patient with insulin resistance syndrome, or inhibition of insulin and IGF-1 receptors via pharmacological reagents increases ADDL levels by exacerbating their aggregation. In healthy cells, activation of insulin and IGF-1 receptor reduces the extracellular ADDLs applied to cells via seemingly the insulin-degrading enzyme activity. Although insulin triggers ADDL internalization, IGF-1 appears to keep ADDLs on the cell surface. Nevertheless, both insulin and IGF-1 reduce ADDL binding, protect synapses from ADDL synaptotoxic effects, and prevent the ADDL-induced surface insulin receptor loss. Our results suggest that dysfunctions of brain insulin and IGF-1 receptors contribute to Abeta aggregation and subsequent synaptic loss.

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Crossref · 10.1074/jbc.m109.011015

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  • Deficient insulin signaling results in impaired removal of Aβ and Aβ oligomers from the extracellular milieu.

    “At the cellular level, deficient insulin signaling results in impaired removal of Aβ (Plum et al., 2005) and Aβ oligomers from the extracellular milieu (Zhao et al., 2009).”

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Authors
Zhao, W.-Q., Lacor, P. N., Chen, H., Lambert, M. P., Quon, M. J., Krafft, G. A., & Klein, W. L.
Affiliations
  • Northwestern University (US)
  • National Institutes of Health (US)
  • Acumen Pharmaceuticals (United States) (US)
Corresponding author
Zhao, Wei-Qin
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2009-07
Volume
284
Issue
28
Pages
18742-18753
ISSN
0021-9258 (ISSN-L)
OpenAlex
W1968530575
Cited by
154
References
88
Citations by year
2025: 10 · 2024: 15 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 9 · 2019: 7 · 2018: 4 · 2017: 11 · 2016: 12 · 2015: 9 · 2014: 11 · 2013: 12 · 2012: 15
FWCI
8.39
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (R01AG022547)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
insulin receptor, IGF-1 receptor, amyloid-beta oligomers, Alzheimer's disease, amyloid-beta aggregation, insulin-degrading enzyme, synaptic toxicity, insulin resistance, receptor internalization, synaptic loss
MeSH terms
Animals, Brain, Humans, Insulin, Insulin Resistance, Insulin-Like Growth Factor I, Models, Biological, Mutation, Neurons, Neurotoxins, Receptor, Insulin, Synapses, Antigens, CD, Amyloid beta-Peptides, NIH 3T3 Cells, Mice, Rats

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