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Antisense oligonucleotides directed against App and Rab5 normalized endosomal Rab activity and reversed DS-AD-linked degenerative phenotypes in the Dp16 mouse model of Down syndrome
Chen XQ, Zuo X, Becker A, Mante M, Florio JB, Jadhav SG, Albay R, Johnstone A et al.. Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025-05-01
Topic: Brain proteins, microglia and lab models
Introduction Down syndrome (DS) markedly raises the risk of Alzheimer's disease (DS-AD). Our findings identified widespread dysregulation of the endolysosomal network (ELN) in DS and DS-AD brains, driven by increased APP gene dose, hyperactivation of RAB5, and elevated levels of guanine nucleotide exchange factors (GEFs) for RABs 7 and 11. Methods We investigated whether increasing APP gene dose and RAB5 hyperactivation contributed to neuropathogenesis and whether a clinically feasible intervention could reverse ELN changes. The Dp16 DS-AD mouse model was treated with a mouse App-specific antisense oligonucleotide (App-ASO) and Rab5-specific ASOs targeting Rab5a and Rab5b. Results App-ASO treatment normalized full-length APP (fl-APP) and its products, RAB5 activity, and downstream RABs 7 and 11 pathways. Rab5-ASOs reduced RAB5 levels and restored endosomal Rab activity. Both ASO treatments mitigated DS-AD-linked pathologies. Discussion These findings highlight ELN dysregulation in DS and the therapeutic potential of ASO-based strategies targeting APP or Rab5 to counteract DS-AD features. Highlights App-ASO treatment reduced the levels of APP and its products and normalized endosomal Rab activity and GEF levels in Dp16 mice. Administration of Rab5-ASOs reduced RAB5 levels and normalized endosomal Rab activity and GEF levels in Dp16 mice. Both ASO treatments were well tolerated and mitigated APP-linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, and synaptic protein loss. App-ASO or Rab5-ASOs reversed established pathological phenotypes in Dp16 mice.
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APA 7th
Chen, X. Q., Zuo, X., Becker, A., Mante, M., Florio, J. B., Jadhav, S. G., et al. (2025). Antisense oligonucleotides directed against App and Rab5 normalized endosomal Rab activity and reversed DS-AD-linked degenerative phenotypes in the Dp16 mouse model of Down syndrome. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1002/alz.70022
Vancouver
Chen XQ, Zuo X, Becker A, Mante M, Florio JB, Jadhav SG, et al. Antisense oligonucleotides directed against App and Rab5 normalized endosomal Rab activity and reversed DS-AD-linked degenerative phenotypes in the Dp16 mouse model of Down syndrome. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2025. doi:10.1002/alz.70022. PMID: 40339155.
BibTeX
@article{chen2025-40339155,
author = {Chen, X. Q. and Zuo, X. and Becker, A. and Mante, M. and Florio, J. B. and Jadhav, S. G. and Albay, R. and Johnstone, A. and others},
title = {{Antisense oligonucleotides directed against App and Rab5 normalized endosomal Rab activity and reversed DS-AD-linked degenerative phenotypes in the Dp16 mouse model of Down syndrome}},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2025},
doi = {10.1002/alz.70022},
pmid = {40339155},
url = {https://doi.org/10.1002/alz.70022}
}
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Key findings
- Our findings identified widespread dysregulation of the endolysosomal network (ELN) in DS and DS-AD brains, driven by increased APP gene dose, hyperactivation of RAB5, and elevated levels of guanine nucleotide exchange factors (GEFs) for RABs 7 and 11.
- Results App-ASO treatment normalized full-length APP (fl-APP) and its products, RAB5 activity, and downstream RABs 7 and 11 pathways.
- Discussion These findings highlight ELN dysregulation in DS and the therapeutic potential of ASO-based strategies targeting APP or Rab5 to counteract DS-AD features.
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Study details
- Evidence strengthLow
How this study scored 48/100
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. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 28 of the 58 points we could judge it on, which is 48 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & dementia : the journal of the Alzheimer's Association) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 “mouse”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40339155) |
| Free to read | 2 / 2 | Free to read |
| Points | 28 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 28 of the 58 points we could judge it on is 48 out of 100. |
| Total | 48 / 100 | — |
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