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Cited by 41Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

APP intracellular domain–WAVE1 pathway reduces amyloid-β production

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Ceglia, Ilaria, Reitz, Christiane, Gresack, Jodi, Ahn, Jung-Hyuck, Bustos, Victor, Bleck, Marina, Zhang, Xiaozhu, Martin, Grant +4 more·2015·Nature Medicine
DOI 10.1038/nm.3924PMC PMC4560977
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Abstract

An increase in amyloid-β (Aβ) production is a major pathogenic mechanism associated with Alzheimer's disease (AD), but little is known about possible homeostatic control of the amyloidogenic pathway. Here we report that the amyloid precursor protein (APP) intracellular domain (AICD) downregulates Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1 or WASF1) as part of a negative feedback mechanism to limit Aβ production. The AICD binds to the Wasf1 promoter, negatively regulates its transcription and downregulates Wasf1 mRNA and protein expression in Neuro 2a (N2a) cells. WAVE1 interacts and colocalizes with APP in the Golgi apparatus. Experimentally reducing WAVE1 in N2a cells decreased the budding of APP-containing vesicles and reduced cell-surface APP, thereby reducing the production of Aβ. WAVE1 downregulation was observed in mouse models of AD. Reduction of Wasf1 gene expression dramatically reduced Aβ levels and restored memory deficits in a mouse model of AD. A decrease in amounts of WASF1 mRNA was also observed in human AD brains, suggesting clinical relevance of the negative feedback circuit involved in homeostatic regulation of Aβ production.

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  • A decrease in WASF1 (human WAVE1 gene) expression was observed in human AD brains compared with healthy control brains and in mouse models of AD compared with controls.

    “A decrease in WASF1 (human WAVE1 gene) expression was observed in human AD brains compared with healthy control brains and in mouse models of AD compared with controls143.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [143]

    The Introductory Paragraph reports lower WASF1 transcript expression in human AD amygdala than in controls, but says this was not observed in the unaffected regions examined. It also reports reduced WAVE1 protein in AD mouse models; the mouse evidence does not establish reduced WASF1 gene expression. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Experimentally reducing WAVE1 expression decreases the budding of APP-containing vesicles from the Golgi and reduces the trafficking of APP to the cell surface, thereby inhibiting Aβ production.

    “Experimentally reducing WAVE1 expression decreases the budding of APP-containing vesicles from the Golgi and reduces the trafficking of APP to the cell surface, thereby inhibiting Aβ production143.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [143]

  • WAVE1 interacts with and colocalizes with APP in the Golgi apparatus.

    “On the other hand, WAVE1 interacts with and colocalizes with APP in the Golgi apparatus.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [143]

  • Reduced WAVE1 expression has a protective role in Alzheimer's disease.

    “WAVE1 KO dramatically reduces Aβ levels and restores memory deficits in APP/PS1 transgenic mice expressing familial mutations in APP (APPswe) and presenilin 1 (PSEN1 ΔE9)146, suggesting a protective role for reduced WAVE1 expression in AD143.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [143]

  • A likely mechanism supported by experimental data is that AICD generated from the amyloidogenic pathway binds to the WAVE1 promoter and negatively regulates its transcription and protein expression.

    “A likely mechanism supported by the experimental data is that the AICD (APP intracellular domain) generated from the amyloidogenic pathway binds to the WAVE1 promoter and negatively regulates its transcription and protein expression143.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [143]

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Authors
Ceglia, I., Reitz, C., Gresack, J., Ahn, J.-H., Bustos, V., Bleck, M., Zhang, X., Martin, G., Simon, S. M., Nairn, A. C., Greengard, P., & Kim, Y.
Affiliations
  • Rockefeller University (US)
  • Columbia University (US)
  • Ewha Womans University (KR)
  • Yale University (US)
Corresponding author
Kim, Yong
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2015-08-17
Volume
21
Issue
9
Pages
1054-1059
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.3924
PMC
PMC4560977
OpenAlex
W1474396053
Cited by
41
References
1
Citations by year
2026: 3 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 4 · 2018: 5 · 2017: 4 · 2016: 5 · 2015: 2
FWCI
3.56
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (AG009464, P50AG047270, AG047270, P01AG009464)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
WAVE1, amyloid-beta production, Alzheimer's disease, negative feedback regulation, APP trafficking, Golgi apparatus, transcriptional repression, memory impairment, APP processing
MeSH terms
Animals, Base Sequence, Cells, Cultured, Humans, Male, Molecular Sequence Data, Signal Transduction, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Protein Structure, Tertiary, Wiskott-Aldrich Syndrome Protein Family, Mice

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