Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ
Open accessAbstract
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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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).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Zhao et al., 2009
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Zhao, N., Liu, C.-C., Van Ingelgom, A. J., Martens, Y. A., Linares, C., Knight, J. A., Painter, M. M., Sullivan, P. M., & Bu, G. (2017) · Neuron · doi:10.1016/j.neuron.2017.09.003 · Cited by 289 · see citing works
Reich, N., & Hölscher, C. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.970925 · Cited by 248 · see citing works
Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer's disease
Paula‐Lima, A. C., Brito‐Moreira, J., & Ferreira, S. T. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12304 · Cited by 170 · see citing works
Amyloid-β oligomers in cellular models of Alzheimer’s disease
Fontana, I. C., Zimmer, A. R., Rocha, A. S., Gosmann, G., Souza, D. O., Lourenco, M. V., Ferreira, S. T., & Zimmer, E. R. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15030 · Cited by 115 · see citing works
Obesity, Insulin Resistance, and Alzheimer's Disease
Hildreth, K. L., Van Pelt, R. E., & Schwartz, R. S. (2012) · Obesity · doi:10.1038/oby.2012.19 · Cited by 86 · see citing works
The neuronal insulin receptor in its environment
Gralle, M. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.13909 · Cited by 64 · see citing works
- 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)
- PMC
- PMC2707198
- 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
- hybrid
- doi.org
- Licence
- 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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