Insulin-degrading Enzyme as a Downstream Target of Insulin Receptor Signaling cascade: Implications for Alzheimer's Disease Intervention
Open accessAbstract
Insulin-degrading enzyme (IDE) is one of the proteins that has been demonstrated to play a key role in degrading beta-amyloid (Abeta) monomer in vitro and in vivo, raising the possibility of upregulating IDE as an approach to reduce Abeta. Little is known, however, about the cellular and molecular regulation of IDE protein. Because one of the main functions of IDE is to degrade insulin, we hypothesized that there is a negative feedback mechanism whereby stimulation of insulin receptor-mediated signaling upregulates IDE to prevent chronic activation of the pathway. We show that treatment of primary hippocampal neurons with insulin increased IDE protein levels by approximately 25%. Insulin treatment also led to phosphatidylinositol-3 (PI3) kinase activation evidenced by Akt phosphorylation, which was blocked by PI3 kinase inhibitors, wortmannin and LY 294002. Inhibition of PI3 kinase abolished the IDE upregulation by insulin, indicating a cause-effect relationship between insulin signaling and IDE upregulation. Further support for this link was provided by the findings that deficient insulin signaling (decreased PI3 kinase subunit P85) was correlated with reduced IDE in Alzheimer's disease (AD) brains and in Tg2576 Swedish amyloid precursor protein transgenic mice fed a safflower oil-enriched ("Bad") diet used to accelerate pathogenesis. Consistent with IDE function in the degradation of Abeta monomer, the IDE decrease in the Bad diet-fed Tg2576 mice was associated with increased Abeta monomer levels. These in vitro and in vivo analyses validate the use of enhanced CNS insulin signaling as a potential strategy for AD intervention to correct the IDE defects occurring in AD.
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Insulin resistance leads to reduced Aβ degradation by insulin-degrading enzyme, promoting Aβ accumulation.
“It is also worth noting that insulin resistance leads to a reduced Aβ degradation by IDE, hence promoting the Aβ accumulation (Ho et al., 2004; Zhao et al., 2004; Petrov et al., 2015).”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Zhao et al., 2004
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- Authors
- Zhao, L., Teter, B., Morihara, T., Lim, G. P., Ambegaokar, S. S., Ubeda, O. J., Frautschy, S. A., & Cole, G. M.
- Affiliations
- University of California, Los Angeles (US)
- VA Greater Los Angeles Healthcare System (US)
- Corresponding author
- Cole, Greg M.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-12-08
- Volume
- 24
- Issue
- 49
- Pages
- 11120-11126
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6730264
- OpenAlex
- W2146405340
- Cited by
- 329
- References
- 40
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 15 · 2023: 12 · 2022: 21 · 2021: 14 · 2020: 11 · 2019: 19 · 2018: 14 · 2017: 22 · 2016: 16 · 2015: 12 · 2014: 19 · 2013: 10 · 2012: 14
- FWCI
- 8.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Southern California
- National Institutes of Health (AG05142)
- University of California, Los Angeles (P50 AG16570)
- National Institute on Aging (R01AG016793, R01 AG16793, P50AG016570, P50-AG 16570, P50-AG05142, R01AG13471, P50AG005142)
- National Cancer Institute (U01CA091343)
- National Center for Complementary and Integrative Health (R01AT003008)
- Topics
- Health Sciences › Medicine › Physiology › 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
- insulin-degrading enzyme, insulin receptor signaling, PI3-kinase, Akt phosphorylation, Alzheimer's disease, hippocampal neurons, negative feedback regulation, p85 regulatory subunit, Tg2576 mice, amyloid precursor protein transgenic mice
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Cells, Cultured, Diabetes Mellitus, Female, Hippocampus, Humans, Insulin, Insulysin, Male, Mice, Transgenic, Middle Aged, Neurons, Receptor, Insulin, Safflower Oil, Signal Transduction, Up-Regulation, Amyloid beta-Peptides, Rats, Sprague-Dawley, Phosphatidylinositol 3-Kinases, Mice, Rats
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