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Regulation of Amyloid Precursor Protein Catabolism Involves the Mitogen-Activated Protein Kinase Signal Transduction Pathway
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Catabolic processing of the amyloid precursor protein (APP) is subject to regulatory control by protein kinases. We hypothesized that this regulation involves sequential activation of the enzymes mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated protein kinase (ERK). In the present investigation, we provide evidence that MEK is critically involved in regulating APP processing by both nerve growth factor and phorbol esters. Western blot analysis of the soluble N-terminal APP derivative APP s demonstrated that the synthetic MEK inhibitor PD 98059 antagonized nerve growth factor stimulation of both APP s production and ERK activation in PC12 cells. Moreover, PD 98059 inhibited phorbol ester stimulation of APP s production and activation of ERK in both human embryonic kidney cells and cortical neurons. Furthermore, overexpression of a kinase-inactive MEK mutant inhibited phorbol ester stimulation of APP secretion and activation of ERK in human embryonic kidney cell lines. Most important, PD 98059 antagonized phorbol ester-mediated inhibition of Aβ secretion from cells overexpressing human APP 695 carrying the “Swedish mutation.” Taken together, these data indicate that MEK and ERK may be critically involved in protein kinase C and nerve growth factor regulation of APP processing. The mitogen-activated protein kinase cascade may provide a novel target for altering catabolic processing of APP.
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“ERK activation has been shown to modulate APP processing and Aβ generation (24, 25, 36).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [36]
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Kwak, Y.-D., Choumkina, E., & Sugaya, K. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.03.054 · Cited by 20
Connop, B. P., Thies, R. L., Beyreuther, K., Ida, N., & Reiner, P. B. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.721457.x · Cited by 19
Self-citationPanax ginseng: A modulator of amyloid, tau pathology, and cognitive function in Alzheimer's disease
Hwang, J., Keum, M., Choe, Y. M., Suh, G., Choi, H., Lee, B. C., Kim, S. G., Kim, H. S., Yi, D., & Kim, J. W. (2025) · Journal of Ginseng Research · doi:10.1016/j.jgr.2025.03.011 · Cited by 21
Binnington, J., & Kalisch, B. E. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04378.x · Cited by 19
Metadata
- Authors
- Mills, J., Laurent Charest, D., Lam, F., Beyreuther, K., Ida, N., Pelech, S. L., & Reiner, P. B.
- Affiliations
- Heidelberg University (DE)
- University of British Columbia (CA)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1997-12-15
- Volume
- 17
- Issue
- 24
- Pages
- 9415-9422
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6573401
- OpenAlex
- W1794943105
- Cited by
- 134
- References
- 87
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 3 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 2 · 2012: 4
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer Society
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid precursor protein, mitogen-activated protein kinase, MEK, ERK, PD98059, nerve growth factor, phorbol ester, protein kinase C, amyloid-beta secretion, Swedish mutation, APP695, PC12 cells, cortical neurons
- MeSH terms
- Alzheimer Disease, Animals, Carcinogens, Cells, Cultured, Cerebral Cortex, Enzyme Inhibitors, Female, Flavonoids, Humans, Kidney, Neurons, Phorbol Esters, Pregnancy, Protein Kinase C, Signal Transduction, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, PC12 Cells, Rats, Sprague-Dawley, Receptors, Nerve Growth Factor, Calcium-Calmodulin-Dependent Protein Kinases, Rats
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