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Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation
Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M et al.. The Journal of biological chemistry, 2004-01-06
Topic: Brain proteins, microglia and lab models
Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic beta-amyloid (Abeta) peptides, is an attractive approach to the treatment of Alzheimer disease. In addition to APP, however, several other gamma-secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by gamma-secretase inhibitors could lead to unintended biological consequences.
Key findings
- In addition to APP, however, several other gamma-secretase substrates have been identified (e.g.
- Notch), and altered processing of these substrates by gamma-secretase inhibitors could lead to unintended biological consequences.
- To study the in vivo consequences of gamma-secretase inhibition, the gamma-secretase inhibitor LY-411,575 was administered to C57BL/6 and TgCRND8 APP transgenic mice for 15 days.
- Although most tissues were unaffected, doses of LY-411,575 that inhibited Abeta production had marked effects on lymphocyte development and on the intestine.
Why it matters
In mice, chronic treatment with the gamma-secretase inhibitor LY-411,575 reduced amyloid-beta production but also altered lymphopoiesis and intestinal cell differentiation. This was an animal study showing unintended biological consequences, so it is not yet known whether this approach would be safe or effective in people.
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Study details
- Evidence strengthLow
How this study scored 48/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on institution's track record, so that was left out: it earned 47 of the 97 points we could judge it on, which is 48 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The Journal of biological chemistry) |
| Journal's citation record | 4 / 4 | Journal of Biological Chemistry: journal h-index 780 (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 | 1 / 5 | 2004 — older than 20 years, still counted |
| 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) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 719 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 30.0 citations a year over 24 year(s) since 2004 |
| Impact for its field and year | 5 / 6 | Cited 22.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 12 other studies in this library |
| Still being cited | 2 / 4 | Cited 38 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Eric M. Parker: h-index 49 (OpenAlex, whole career) |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 0 institution(s) in 0 countries — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 14709552) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 47 / 97 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 47 of the 97 points we could judge it on is 48 out of 100. |
| Total | 48 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1074/jbc.m311652200
- PubMed: 14709552
- Original source →
- Free full text: Journal of Biological Chemistry →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Wong, G. T., Manfra, D., Poulet, F. M., Zhang, Q., Josien, H., Bara, T., et al. (2004). Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. The Journal of biological chemistry. https://doi.org/10.1074/jbc.m311652200
Vancouver
Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. The Journal of biological chemistry. 2004. doi:10.1074/jbc.m311652200. PMID: 14709552.
BibTeX
@article{wong2004-14709552,
author = {Wong, G. T. and Manfra, D. and Poulet, F. M. and Zhang, Q. and Josien, H. and Bara, T. and Engstrom, L. and Pinzon-Ortiz, M. and others},
title = {{Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation}},
journal = {The Journal of biological chemistry},
year = {2004},
doi = {10.1074/jbc.m311652200},
pmid = {14709552},
url = {https://doi.org/10.1074/jbc.m311652200}
}
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