Rac1 changes the substrate specificity of γ-secretase between amyloid precursor protein and Notch1
Abstract
Beta amyloid peptide is generated from amyloid precursor protein (APP) by proteolytic cleavage of beta- and gamma-secretases, and plays a critical role in the pathogenesis of Alzheimer's disease. Since gamma-secretase cleaves several proteins including APP and Notch in a number of cell types, it is important to understand the conditions determining gamma-secretase substrate specificity. In the present study, inhibition of Rac1 attenuated gamma-secretase activity for APP, resulting in decreased production of the APP intracellular domain but accumulated C-terminal fragments (APP-CTF). In contrast, Rac1 inhibitor, NSC23766 increased production of the Notch1 intracellular domain but slightly decreased the ectodomain-shed form of Notch1 (NotchDeltaE). To elucidate the mechanism underlying these observations, we performed co-immunoprecipitation experiments to analyze the interaction between Rac1 and presenilin1 (PS1), a component of the gamma-secretase complex. Inhibition of Rac1 enhanced its interaction with PS1. Under the same condition, PS1 interacted more strongly with NotchDeltaE than with APP-CTF. Our results suggested that PS1 determines the preferred substrate for gamma-secretase between APP and Notch1, depending on the activation status of Rac1.
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In mouse primary hippocampal neurons, RAC1 inhibition with compound NSC23766 leads to attenuated γ-secretase activity, reduction in cellular APP, and subsequent β-amyloid plaque formation.
“This can be inferred from mouse primary hippocampal neuronal experiments, where RAC1 inhibition with compound NSC23766 leads to attenuated γ-secretase activity, resulting in a reduction in cellular amyloid precursor protein (APP) and subsequent β-amyloid plaque formation, a hallmark of Alzheimer’s disease (AD) (29).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [29]
The activation of RAC1 in a cell line or primary cultured cortical neurons increased Aβ levels and tau hyperphosphorylation.
“The activation of RAC1 in a cell line or primary cultured cortical neurons increased Aβ levels and tau hyperphosphorylation.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [151]
Inhibition of RAC1 attenuated γ-secretase activity for APP.
“Inhibition of RAC1 attenuated γ-secretase activity for APP151.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [151]
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References 32 · Cited by 32
- Authors
- Boo, J. H., Sohn, J. H., Kim, J. E., Song, H., & Mook-Jung, I.
- Affiliations
- Seoul National University (KR)
- ORCID
- Kim, Ji Eun
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 372
- Issue
- 4
- Pages
- 913-917
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2007696560
- Cited by
- 32
- References
- 32
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 2 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 4 · 2013: 5
- FWCI
- 1.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- 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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Rac1, gamma-secretase, substrate specificity, amyloid precursor protein, Notch1, presenilin 1, APP intracellular domain, APP C-terminal fragments, amyloid-beta, Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Aminoquinolines, Animals, Cell Line, Chlorocebus aethiops, Enzyme Activation, Humans, Pyrimidines, Substrate Specificity, Drug Design, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Sequence Deletion, Protein Structure, Tertiary, COS Cells, rac1 GTP-Binding Protein, Receptor, Notch1, Presenilin-1, Amyloid Precursor Protein Secretases
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