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The neuropeptide PACAP promotes ?‐secretase pathway for processing Alzheimer amyloid precursor protein
Abstract
The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has neurotrophic as well as anti-apoptotic properties and is involved in learning and memory processes. Its specific G protein-coupled receptor PAC1 is expressed in several central nervous system (CNS) regions, including the hippocampal formation. Here we examined the effect of PAC1 receptor activation on alpha-secretase cleavage of the amyloid precursor protein (APP) and the production of secreted APP (APPsalpha). Stimulation of endogenously expressed PAC1 receptors with PACAP in human neuroblastoma cells increased APPsalpha secretion, which was completely inhibited by the PAC1 receptor specific antagonist PACAP-(6-38). In HEK cells stably overexpressing functional PAC1 receptors, PACAP-27 and PACAP-38 strongly stimulated alpha-secretase cleavage of APP. The PACAP-induced APPsalpha production was dose dependent and saturable. This increase of alpha-secretase activity was completely abolished by hydroxamate-based metalloproteinase inhibitors, including a preferential ADAM 10 inhibitor. By using several specific protein kinase inhibitors, we show that the MAP-kinase pathway [including extracellular-regulated kinase (ERK) 1 and ERK2] and phosphatidylinositol 3-kinase mediate the PACAP-induced alpha-secretase activation. Our findings provide evidence for a role of the neuropeptide PACAP in stimulation of the nonamyloidogenic pathway, which might be related to its neuroprotective properties.
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“ERK, a mitogen-activated protein kinase (MAPK), has been shown to suppress Aβ production in vitro and in vivo by altering secretase activity (24, 25).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [25]
In the citing paper
“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 [25]
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Metadata
- Authors
- Kojro, E., Postina, R., Buro, C., Meiringer, C., Gehrig‐Burger, K., & Fahrenholz, F.
- Affiliations
- Institute of Biochemistry Johannes Gutenberg University D‐55128 Mainz Germany
- Johannes Gutenberg University Mainz (DE)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2006-01-09
- Volume
- 20
- Issue
- 3
- Pages
- 512-514
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W1984933995
- Cited by
- 118
- References
- 65
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 4 · 2017: 9 · 2016: 5 · 2015: 6 · 2014: 5 · 2013: 3 · 2012: 12
- FWCI
- 5.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (KO 2104/2-1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Peptidase Inhibition and Analysis
- Keywords
- PACAP, PAC1 receptor, amyloid precursor protein, alpha-secretase, ADAM10, non-amyloidogenic pathway, mitogen-activated protein kinase, ERK1/2, phosphatidylinositol 3-kinase, Alzheimer's disease, neuroprotection, G protein-coupled receptor signaling
- MeSH terms
- ADAM10 Protein, ADAM17 Protein, Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Adenylyl Cyclases, Alzheimer Disease, Amino Acid Sequence, Androstadienes, Animals, Calcium, Cell Line, Enzyme Activation, Humans, Kidney, Membrane Proteins, Molecular Sequence Data, Neuroblastoma, Endopeptidases, Phosphorylation, Protein Kinase C, Protein Processing, Post-Translational, Recombinant Fusion Proteins, Transfection, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, PC12 Cells, Cyclic AMP Response Element-Binding Protein, Cyclic AMP-Dependent Protein Kinases, Phosphatidylinositol 3-Kinases, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Pituitary Adenylate Cyclase-Activating Polypeptide, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I, Rats, ADAM Proteins, Amyloid Precursor Protein Secretases
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