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45/100

✓ Peer-reviewed alzhub usefulness score 45 out of 100. Risk genes beyond APOE

Topic: Brain proteins, microglia and lab models

γ-Secretase modulators (GSMs) represent an emerging oral therapy for preventing and targeting Aβ-amyloidosis in Alzheimer disease. Aβ is a family of peptides of varying lengths where both the total and relative amounts of the individual Aβ peptides affect the process of amyloidosis. In contrast to inhibitors of Aβ synthesis, GSMs do not affect the total amount of Aβ peptides generated but decrease longer more amyloidogenic Aβ species while increasing the production of shorter less amyloidogenic Aβ peptides. In this study, we investigated how this modulation of Aβ production affects Aβ plaque dynamics in the brains of APP/PS1dE9 transgenic mice. Similar to studies with different inhibitors of Aβ synthesis, we found that 28 days of once-daily oral treatment with the GSM AZ4126 (100 μmol/kg) resulted in a strong reduction in plaque formation and plaque growth. In addition, and in contrast to Aβ production inhibitors, the GSM AZ4126 caused a significant reduction in the size of established Aβ plaques. Moreover, the antiamyloidogenic activity was accompanied by a marked reduction in brain interstitial fluid Aβ40 and Aβ42 and an increase in Aβ37. Treatment of induced pluripotent stem cell-derived cortical neurons with the GSM AZ4126 reduced secreted Aβ40 and Aβ42 dose-dependently and with a complementary increase in Aβ37 and Aβ38. These studies unravel a previously unknown antiamyloidogenic effect of GSMs, suggesting that they promote the clearance of already established Aβ pathology in addition to their inhibition of Aβ amyloid formation. SIGNIFICANCE STATEMENT: Immunotherapies promoting Aβ-amyloid clearance have shown efficacy in early Alzheimer disease, but complementary Aβ targeting therapeutic approaches are needed. γ-Secretase modulators (GSMs) target Aβ production with an effective and tolerable mechanism. This study demonstrates that a GSM not only inhibits Aβ-amyloid formation but also promotes Aβ-plaque clearance in experiments conducted in an Aβ-amyloidosis mouse model and supports further development of GSMs as an effective oral treatment for Alzheimer disease.

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APA 7th

Nordvall, G., Yan, P., Agholme, L., Lundkvist, J., Sandin, J., Biverstål, H., et al. (2025). γ-Secretase modulation inhibits amyloid plaque formation and growth and stimulates plaque regression in amyloid precursor protein/presenilin-1 mice. Journal of Pharmacology and Experimental Therapeutics. https://doi.org/10.1016/j.jpet.2025.103400

Vancouver

Nordvall G, Yan P, Agholme L, Lundkvist J, Sandin J, Biverstål H, et al. γ-Secretase modulation inhibits amyloid plaque formation and growth and stimulates plaque regression in amyloid precursor protein/presenilin-1 mice. Journal of Pharmacology and Experimental Therapeutics. 2025. doi:10.1016/j.jpet.2025.103400. PMID: 40054389.

BibTeX

@article{nordvall2025-40054389,
  author  = {Nordvall, Gunnar and Yan, Ping and Agholme, Lotta and Lundkvist, Johan and Sandin, Johan and Biverstål, Henrik and Winblad, Bengt G. and Zetterberg, Henrik and others},
  title   = {{γ-Secretase modulation inhibits amyloid plaque formation and growth and stimulates plaque regression in amyloid precursor protein/presenilin-1 mice}},
  journal = {Journal of Pharmacology and Experimental Therapeutics},
  year    = {2025},
  doi     = {10.1016/j.jpet.2025.103400},
  pmid    = {40054389},
  url     = {https://doi.org/10.1016/j.jpet.2025.103400}
}

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Key findings

Similar to studies with different inhibitors of Aβ synthesis, we found that 28 days of once-daily oral treatment with the GSM AZ4126 (100 μmol/kg) resulted in a strong reduction in plaque formation and plaque growth.
In addition, and in contrast to Aβ production inhibitors, the GSM AZ4126 caused a significant reduction in the size of established Aβ plaques.
These studies unravel a previously unknown antiamyloidogenic effect of GSMs, suggesting that they promote the clearance of already established Aβ pathology in addition to their inhibition of Aβ amyloid formation.

Why it matters

In APP/PS1dE9 transgenic mice, 28 days of oral treatment with the gamma-secretase modulator AZ4126 reduced plaque formation and growth and also shrank established plaques, with changes in Aβ peptide levels. These are animal and cell results, so it is too early to say whether this approach treats or prevents Alzheimer's disease in people.

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Study details

Evidence strengthLow

How this study scored 45/100

Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomized / blinded because the record does not state it.

Component	Points	Why
Journal tier	7 / 10	Tier 3 — peer-reviewed journal (Journal of Pharmacology and Experimental Therapeutics)
Journal's citation record	3 / 4	Journal of Pharmacology and Experimental Therapeutics: journal h-index 327 (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	Laboratory or animal study (title names “mice”) — scores zero
Randomized / blinded	0 / 2	No randomization or blinding stated — scores zero (not stated in the record — scored 0)
Times cited	2 / 7	Cited 7 times (OpenAlex, 2026-10-10)
Citations per year	1 / 5	2.3 citations a year over 3 year(s) since 2025
Impact for its field and year	3 / 6	Cited 3.8× the average for papers of its field and year (OpenAlex FWCI)
Cited by studies here	1 / 6	Cited by 1 other studies in this library
Still being cited	1 / 4	Cited 7 times in 2024–2026 (2026 still in progress; OpenAlex)
Senior author's track record	3 / 4	Last-listed author Jin‐Moo Lee: h-index 77 (OpenAlex, whole career)
Institution's track record	2 / 3	University College London: institution h-index 2,029 (OpenAlex)
Multicenter collaboration	3 / 3	OpenAlex lists 12 institution(s) in 3 countries
Indexed in PubMed	2 / 2	Indexed in PubMed (PMID 40054389)
Free to read	2 / 2	Free to read
Total	45 / 100	—

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