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Cited by 47Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase Signaling

Novel GαS-Protein Signaling Associated with Membrane-Tethered Amyloid Precursor Protein Intracellular Domain

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Deyts, Carole, Vetrivel, Kulandaivelu S., Das, Shibandri, Shepherd, Yumiko M., Dupré, Denis J., Thinakaran, Gopal, Parent, Angèle T.·2012·The Journal of Neuroscience
DOI 10.1523/jneurosci.5433-11.2012PMC PMC3567462
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Abstract

Numerous physiological functions, including a role as a cell surface receptor, have been ascribed to Alzheimer's disease-associated amyloid precursor protein (APP). However, detailed analysis of intracellular signaling mediated by APP in neurons has been lacking. Here, we characterized intrinsic signaling associated with membrane-bound APP C-terminal fragments, which are generated following APP ectodomain release by α- or β-secretase cleavage. We found that accumulation of APP C-terminal fragments or expression of membrane-tethered APP intracellular domain results in adenylate cyclase-dependent activation of PKA (protein kinase A) and inhibition of GSK3β signaling cascades, and enhancement of axodendritic arborization in rat immortalized hippocampal neurons, mouse primary cortical neurons, and mouse neuroblastoma. We discovered an interaction between BBXXB motif of APP intracellular domain and the heterotrimeric G-protein subunit Gα S, and demonstrate that Gα S coupling to adenylate cyclase mediates membrane-tethered APP intracellular domain-induced neurite outgrowth. Our study provides clear evidence that APP intracellular domain can have a nontranscriptional role in regulating neurite outgrowth through its membrane association. The novel functional coupling of membrane-bound APP C-terminal fragments with Gα S signaling identified in this study could impact several brain functions such as synaptic plasticity and memory formation.

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  • Accumulation of sAPPβ and/or β-CTF may affect long-term potentiation and memory acquisition in mouse models.

    “For example, the accumulation of amino-terminal-soluble APPβ (sAPPβ) and/or β-carboxyl-terminal fragments (β-CTF) may affect long-term potentiation (LTP) [5] and memory acquisition in mouse models [6].”

    From Normal cognition in transgenic BRI2-Aβ mice (2013) · cites this paper as [5]

    The Discussion (page not provided) proposes that signaling from accumulated APP-CTF could regulate synaptic plasticity and memory formation, which supports the claim’s cautious wording about a possible effect. The Results examine neurite outgrowth in cells and cultured neurons, not memory acquisition in mouse models; the cited passages also do not establish an effect of sAPPβ. (LLM, conf=0.82)

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Cited by

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Authors
Deyts, C., Vetrivel, K. S., Das, S., Shepherd, Y. M., Dupré, D. J., Thinakaran, G., & Parent, A. T.
Affiliations
  • University of Chicago (US)
  • Dalhousie University (CA)
Corresponding author
Parent, Angèle T.
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2012-02-01
Volume
32
Issue
5
Pages
1714-1729
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.5433-11.2012
PMC
PMC3567462
OpenAlex
W2084323091
Cited by
47
References
0
Citations by year
2026: 3 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 4 · 2017: 8 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 9 · 2012: 1
FWCI
4.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • Alzheimer's Association (IIRG-06-26148, AG019070, NS055223)
  • National Institutes of Health
  • National Institute on Aging (R01AG019070, AG019070)
  • National Institute of Neurological Disorders and Stroke (R01NS055223, NS055223)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
amyloid precursor protein, APP intracellular domain, Gs protein, heterotrimeric G protein signaling, APP C-terminal fragments, adenylate cyclase, protein kinase A, GSK3β, neurite outgrowth, hippocampal neurons, cortical neurons, Alzheimer's disease, synaptic plasticity, memory formation
MeSH terms
Adenylyl Cyclases, Amino Acid Sequence, Animals, Cell Line, Transformed, Cell Membrane, Chlorocebus aethiops, Female, Intracellular Membranes, Male, Molecular Sequence Data, Signal Transduction, Neurites, Amyloid beta-Protein Precursor, Protein Structure, Tertiary, GTP-Binding Protein alpha Subunits, Gs, COS Cells, Cell Line, Tumor, Cell Proliferation, Mice, Rats

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