Cited by 134Alzheimer's disease research and treatmentsProtein Kinase Regulation and GTPase SignalingNeuroinflammation and Neurodegeneration Mechanisms

Regulation of Amyloid Precursor Protein Catabolism Involves the Mitogen-Activated Protein Kinase Signal Transduction Pathway

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Mills, Julia, Laurent Charest, David, Lam, Fred, Beyreuther, Konrad, Ida, Nobuo, Pelech, Steven L., Reiner, Peter B.·1997·The Journal of Neuroscience

Abstract

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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Crossref · 10.1523/jneurosci.17-24-09415.1997

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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
Published
1997-12-15
Volume
17
Issue
24
Pages
9415-9422
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
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
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
  • Health Sciences › Medicine › Physiology › 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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