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γ-Secretase Modulator BPN15606 Reduced Aβ42 and Aβ40 and Countered Alzheimer-Related Pathologies in a Mouse Model of Down Syndrome
Chen XQ, Becker A, Albay R, Nguyen PD, Karachentsev D, Roberts AJ, Rynearson KD, Tanzi RE et al.. Annals of neurology, 2024-05-15
Topic: Brain proteins, microglia and lab models
Objectives Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS-AD. How the increased APP gene dose acts and which APP products are responsible for DS-AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of γ-secretase modulators that promote γ-site cleavages by the γ-secretase complex, resulting in lower levels of the Aβ42 and Aβ40 peptides. Methods Ts65Dn mice, which serve as a model of DS, were treated via oral gavage with 10 mg/kg/weekday of BPN15606 (a potent and novel pyridazine-containing γ-secretase modulators). Treatment started at 3 months-of-age and lasted for 4 months. Results Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Aβ40 and Aβ42 in the cortex and hippocampus; it had no effect on full-length APP or its C-terminal fragments in either 2 N or Ts65Dn mice. Importantly, the levels of total amyloid-β were not impacted, pointing to BPN15606-mediated enhancement of processivity of γ-secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits. Interpretation Our findings point to the involvement of increased levels of Aβ42 and/or Aβ40 in contributing to several molecular and cognitive traits associated with DS-AD. They speak to increased dosage of the APP gene acting through heightened levels of Aβ42 and/or Aβ40 as supporting pathogenesis. These findings further the interest in the potential use of γ-secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024;96:390-404.
Key findings
- Objectives Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS-AD.
- Results Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Aβ40 and Aβ42 in the cortex and hippocampus; it had no effect on full-length APP or its C-terminal fragments in either 2 N or Ts65Dn mice.
- Interpretation Our findings point to the involvement of increased levels of Aβ42 and/or Aβ40 in contributing to several molecular and cognitive traits associated with DS-AD.
- These findings further the interest in the potential use of γ-secretase modulators for treating and possibly preventing AD in individuals with DS.
Why it matters
In a mouse model of Down syndrome, the compound BPN15606 lowered levels of Aβ42 and Aβ40 and normalized several Alzheimer-related cellular changes. This is an animal study, so it does not yet show any treatment, cure or prevention of Alzheimer's disease in people.
Study details
- Evidence strengthLow
How this study scored 43/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Annals of neurology) |
| Journal's citation record | 3 / 4 | Annals of Neurology: journal h-index 437 (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 | 2024 — 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 “mouse”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 14 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.5 citations a year over 4 year(s) since 2024 |
| Impact for its field and year | 3 / 6 | Cited 3.3× 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 | 1 / 4 | Cited 14 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author William Cary Mobley: h-index 84 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Massachusetts General Hospital: institution h-index 2,057 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 38747498) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 43 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Chen, X. Q., Becker, A., Albay, R., Nguyen, P. D., Karachentsev, D., Roberts, A. J., et al. (2024). γ-Secretase Modulator BPN15606 Reduced Aβ42 and Aβ40 and Countered Alzheimer-Related Pathologies in a Mouse Model of Down Syndrome. Annals of neurology. https://doi.org/10.1002/ana.26958
Vancouver
Chen XQ, Becker A, Albay R, Nguyen PD, Karachentsev D, Roberts AJ, et al. γ-Secretase Modulator BPN15606 Reduced Aβ42 and Aβ40 and Countered Alzheimer-Related Pathologies in a Mouse Model of Down Syndrome. Annals of neurology. 2024. doi:10.1002/ana.26958. PMID: 38747498.
BibTeX
@article{chen2024-38747498,
author = {Chen, X. Q. and Becker, A. and Albay, R. and Nguyen, P. D. and Karachentsev, D. and Roberts, A. J. and Rynearson, K. D. and Tanzi, R. E. and others},
title = {{γ-Secretase Modulator BPN15606 Reduced Aβ42 and Aβ40 and Countered Alzheimer-Related Pathologies in a Mouse Model of Down Syndrome}},
journal = {Annals of neurology},
year = {2024},
doi = {10.1002/ana.26958},
pmid = {38747498},
url = {https://doi.org/10.1002/ana.26958}
}
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