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γ-Secretase exosites as targets for substrate-selective lowering of Aβ generation
Riki Maruyama, Akio Fukumori, Satoru Funamoto, Ken Okada, Shoshin Akamine, Kanta Yanagida, Mitsuru Shinohara, Naoyuki Sato et al.. Structure, 2025-12-19
Topic: Brain proteins, microglia and lab models
Intramembrane proteolysis by γ-secretase is critically implicated in Alzheimer disease pathogenesis by processing of its amyloid precursor protein substrate C99 into harmful amyloid-β peptide (Aβ) species. Recruitment of C99 involves binding of its N-terminal extracellular domain to exosites in γ-secretase. However, the role of these interactions has been elusive. Here, we show that the N-terminally shorter extracellular domain of the non-amyloidogenic C83 substrate also interacts with γ-secretase exosites, but more weakly. Moreover, we found that bulky aromatic mutations within the 16 amino acid extension of C99 interfere with exosite binding and inhibit substrate cleavage. Likewise, peptides binding to the C99 N-terminus that selectively inhibit Aβ production in vitro and in vivo interfere with exosite binding of C99. Our data show that exosite interactions of the C99 N-terminal region with γ-secretase can impact substrate cleavage and indicate that interfering with exosite interactions of C99 may provide a means for modulating amyloidogenic substrate processing.
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APA 7th
Maruyama, R., Fukumori, A., Funamoto, S., Okada, K., Akamine, S., Yanagida, K., et al. (2025). γ-Secretase exosites as targets for substrate-selective lowering of Aβ generation. Structure. https://doi.org/10.1016/j.str.2025.11.010
Vancouver
Maruyama R, Fukumori A, Funamoto S, Okada K, Akamine S, Yanagida K, et al. γ-Secretase exosites as targets for substrate-selective lowering of Aβ generation. Structure. 2025. doi:10.1016/j.str.2025.11.010. PMID: 41418776.
BibTeX
@article{maruyama2025-41418776,
author = {Maruyama, Riki and Fukumori, Akio and Funamoto, Satoru and Okada, Ken and Akamine, Shoshin and Yanagida, Kanta and Shinohara, Mitsuru and Sato, Naoyuki and others},
title = {{γ-Secretase exosites as targets for substrate-selective lowering of Aβ generation}},
journal = {Structure},
year = {2025},
doi = {10.1016/j.str.2025.11.010},
pmid = {41418776},
url = {https://doi.org/10.1016/j.str.2025.11.010}
}
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Key findings
- Moreover, we found that bulky aromatic mutations within the 16 amino acid extension of C99 interfere with exosite binding and inhibit substrate cleavage.
- Our data show that exosite interactions of the C99 N-terminal region with γ-secretase can impact substrate cleavage and indicate that interfering with exosite interactions of C99 may provide a means for modulating amyloidogenic substrate processing.
Why it matters
This laboratory study shows that interactions between the C99 N-terminal region and gamma-secretase exosites affect substrate cleavage, and that interfering with these interactions can modulate amyloidogenic processing. It suggests a possible approach for lowering amyloid-beta generation, but no treatment in humans is tested.
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Study details
- Evidence strengthLow
How this study scored 35/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 34 of the 96 points we could judge it on, which is 35 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Structure) |
| Journal's citation record | 2 / 4 | Structure: journal h-index 237 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 2 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 2 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 1 / 3 | Ludwig-Maximilians-Universität München: institution h-index 1,224 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41418776) |
| Free to read | 2 / 2 | Free to read |
| Points | 34 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 34 of the 96 points we could judge it on is 35 out of 100. |
| Total | 35 / 100 | — |
What each of these 20 components measures, and what this score is not →
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