γ-Secretase: Successive Tripeptide and Tetrapeptide Release from the Transmembrane Domain of β-Carboxyl Terminal Fragment
Open accessAbstract
Amyloid β protein (Aβ), a pathogenic molecule associated with Alzheimer's disease, is produced by γ-secretase, which cleaves the β-carboxyl terminal fragment (βCTF) of β-amyloid precursor protein in the middle of its transmembrane domain. How the cleavage proceeds within the membrane has long been enigmatic. We hypothesized previously that βCTF is cleaved first at the membrane–cytoplasm boundary, producing two long Aβs, Aβ 48 and Aβ 49, which are processed further by releasing three residues at each step to produce Aβ 42 and Aβ 40, respectively. To test this hypothesis, we used liquid chromatography tandem mass spectrometry (LC-MS/MS) to quantify the specific tripeptides that are postulated to be released. Using CHAPSO (3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxyl-1-propanesulfonate)-reconstituted γ-secretase system, we confirmed that Aβ 49 is converted to Aβ 43/40 by successively releasing two or three tripeptides and that Aβ 48 is converted to Aβ 42/38 by successively releasing two tripeptides or these plus an additional tetrapeptide. Most unexpectedly, LC-MS/MS quantification revealed an induction period, 3–4 min, in the generation of peptides. When extrapolated, each time line for each tripeptide appears to intercept the same point on the x-axis. According to numerical simulation based on the successive reaction kinetics, the induction period exists. These results strongly suggest that Aβ is generated through the stepwise processing of βCTF by γ-secretase.
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γ-secretase cleavage of C99 releases pathogenic amyloidogenic Aβ associated with Alzheimer's disease.
“The subsequent cleavage of C99 by γ-secretase leads to the release of the pathogenic amyloidogenic beta-amyloid peptide (Aβ) associated with Alzheimer’s disease (Qi-Takahara et al., 2005; Takami et al., 2009; Tomita, 2014).”
From Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production (2020) · cites this paper as Takami et al., 2009
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- Authors
- Takami, M., Nagashima, Y., Sano, Y., Ishihara, S., Morishima-Kawashima, M., Funamoto, S., & Ihara, Y.
- Affiliations
- Doshisha University (JP)
- The University of Tokyo (JP)
- Eisai (Japan) (JP)
- Corresponding author
- Ihara, Yasuo
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-10-14
- Volume
- 29
- Issue
- 41
- Pages
- 13042-13052
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6665297
- OpenAlex
- W2088989293
- Cited by
- 498
- References
- 3
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 30 · 2023: 35 · 2022: 41 · 2021: 36 · 2020: 40 · 2019: 39 · 2018: 23 · 2017: 34 · 2016: 40 · 2015: 23 · 2014: 29 · 2013: 27 · 2012: 35
- FWCI
- 14.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hokkaido University
- Information-Technology Promotion Agency
- Japan Science and Technology Agency
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- gamma-secretase, amyloid-beta, amyloid precursor protein, induction period, reaction kinetics, Alzheimer's disease
- MeSH terms
- Analysis of Variance, Animals, Cell Membrane, Cholic Acids, Chromatography, Liquid, Cricetulus, Detergents, Cricetinae, Models, Biological, Oligopeptides, Peptide Fragments, Substrate Specificity, Time Factors, Amyloid beta-Peptides, CHO Cells, Amyloid beta-Protein Precursor, Protein Structure, Tertiary, Immunoprecipitation, Tandem Mass Spectrometry, Amyloid Precursor Protein Secretases
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