Longer Forms of Amyloid β Protein: Implications for the Mechanism of Intramembrane Cleavage by γ-Secretase
Open accessAbstract
γ-Cleavage of β-amyloid precursor protein (APP) in the middle of the cell membrane generates amyloid β protein (Aβ), and ϵ-cleavage, ∼10 residues downstream of the γ-cleavage site, releases the APP intracellular domain (AICD). A significant link between generation of Aβ and AICD and failure to detect AICD41-99 led us to hypothesize that ϵ-cleavage generates longer Aβs, which are then processed to Aβ40/42. Using newly developed gel systems and an N-end-specific monoclonal antibody, we have identified the longer Aβs (Aβ1-43, Aβ1-45, Aβ1-46, and Aβ1-48) within the cells and in brain tissues. The production of these longer Aβs as well as Aβ40/42 is presenilin dependent and is suppressed by {1 S-benzyl-4 R-[1 S-carbamoyl-2-phenylethylcarbamoyl-1 S-3-methylbutylcarbamoyl]-2 R-hydroxy-5-phenylpentyl}carbamic acid tert-butyl ester, a transition state analog inhibitor for aspartyl protease. In contrast,N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, a potent dipeptide γ-secretase inhibitor, builds up Aβ1-43 and Aβ1-46 intracellularly, which was also confirmed by mass spectrometry. Notably, suppression of Aβ40 appeared to lead to an increase in Aβ43, which in turn brings an increase in Aβ46, in a dose-dependent manner. We therefore propose an α-helical model in which longer Aβ species generated by ϵ-cleavage is cleaved at every three residues in its carboxyl portion.
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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 Qi-Takahara et al., 2005
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- Authors
- Qi-Takahara, Y., Morishima-Kawashima, M., Tanimura, Y., Dolios, G., Hirotani, N., Horikoshi, Y., Kametani, F., Maeda, M., Saido, T. C., Wang, R., & Ihara, Y.
- Affiliations
- The University of Tokyo (JP)
- Icahn School of Medicine at Mount Sinai (US)
- Tokyo Institute of Psychiatry (JP)
- RIKEN (JP)
- Corresponding author
- Ihara, Yasuo
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-01-12
- Volume
- 25
- Issue
- 2
- Pages
- 436-445
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725472
- OpenAlex
- W2097750046
- Cited by
- 391
- References
- 5
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 17 · 2023: 20 · 2022: 14 · 2021: 14 · 2020: 17 · 2019: 22 · 2018: 14 · 2017: 15 · 2016: 24 · 2015: 16 · 2014: 20 · 2013: 31 · 2012: 29
- FWCI
- 13.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- National Institutes of Health
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, gamma-secretase, APP intracellular domain, presenilin, aspartyl protease inhibitors, Aβ40, intramembrane cleavage, Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cell Line, Cricetulus, Dipeptides, Cricetinae, Humans, Male, Membrane Proteins, Mice, Transgenic, Endopeptidases, Subcellular Fractions, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Protein Structure, Secondary, Protein Structure, Tertiary, Amino Acid Motifs, Mice, Presenilin-1, Presenilin-2, Amyloid Precursor Protein Secretases
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