Evidence map›Paper›PMID 40339155›Full record

ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025

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.

Xu-Qiao Chen, Xinxin Zuo, Ann Becker, Michael Mante, Jazmin B Florio, Satish G Jadhav, Ricardo Albay, Aaron Johnstone, Dmitry Karachentsev, Robert Rissman and 3 more

Abstract read
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In one paragraph

Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.

0numbers the graph read from it
0cells of the map it votes in
10citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

10 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
  4. Review
  5. Article
  6. Review
  7. Tau pathology differs by sex in Alzheimer's disease in Down syndrome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
  8. Neuronal Deletion ofBiomolecules · 2025
    Article
  9. Article
  10. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Xu-Qiao ChenDepartment of Neurosciences, University of California San Diego, La Jolla, California, USA.
Xinxin ZuoDepartment of Neurosciences, University of California San Diego, La Jolla, California, USA.
Ann BeckerDepartment of Neurosciences, University of California San Diego, La Jolla, California, USA.
Michael ManteDepartment of Neurosciences, University of California San Diego, La Jolla, California, USA.
Jazmin B FlorioDepartment of Neurosciences, University of California San Diego, La Jolla, California, USA.
Satish G JadhavDepartment of Cellular & Molecular Medicine, University of California San Diego, La Jolla, California, USA.
Ricardo AlbayDepartment of Neurosciences, University of California San Diego, La Jolla, California, USA.
Aaron JohnstoneDepartment of Neurosciences, University of California San Diego, La Jolla, California, USA.
Dmitry KarachentsevDepartment of Neurosciences, University of California San Diego, La Jolla, California, USA.
Robert RissmanDepartment of Neurosciences, University of California San Diego, La Jolla, California, USA.
Hien ZhaoIonis Pharmaceuticals Inc., Carlsbad, California, USA.
Steven F DowdyDepartment of Cellular & Molecular Medicine, University of California San Diego, La Jolla, California, USA.
William C MobleyDepartment of Neurosciences, University of California San Diego, La Jolla, California, USA.

Funding

Vascular Contributions to Dementia and Genetic Risk Factors for Alzheimer's DiseaseP01AG052350 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Daniel A Nation, ARTHUR W TOGA · 2016 to 2026
$28.4M
USCADRC Diversity Supplement PachicanoP30AG066530 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI HELENA Chang CHUI · 2020 to 2026
$27.8M
Multiplexed Single Nucleus RNA and ATAC-seq Sequencing and Cortical Organoids: Transformative Insights into Down SyndromeR01AG070154 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MOBLEY, WILLIAM C, ROSENFELD, MICHAEL G · 2020 to 2020
$5.0M
Antisense Oligonucleotides targeting APP to prevent neurodegeneration in models of Down Syndrome and Alzheimer's diseaseR01AG061151 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MOBLEY, WILLIAM C · 2019 to 2023
$3.4M
Treating with Gamma-Secretase Modulators to Prevent Neurodegeneration in Mouse Models of Down Syndrome and Alzheimer DiseaseR01AG055523 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MOBLEY, WILLIAM C · 2018 to 2022
$3.2M
Cure Alzheimer's Fund UCSD2019-2544DH Chen Foundation R-86U55ANIA NIH HHS P01 AG052350NIA NIH HHS P30 AG066530NIA NIH HHS R01 AG055523NIA NIH HHS R01 AG061151NIA NIH HHS R01 AG070154NIH HHS R01AG055523NIH HHS R01AG061151NIH HHS R01AG070154
6 · The paper itself

Abstract

introductionDown 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.

methodsWe 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.

resultsApp-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.

Indexed as

Alzheimer DiseaseAmyloid beta-Protein PrecursorDown SyndromeEndosomesOligonucleotides, Antisenserab5 GTP-Binding Proteinsrab GTP-Binding ProteinsAnimalsBrainDisease Models, AnimalHumansMiceMice, TransgenicPhenotypeAmyloid beta-Protein PrecursorOligonucleotides, Antisenserab5 GTP-Binding Proteinsrab GTP-Binding ProteinsAlzheimer's diseaseApp‐ASODown syndromeDp16 mouseendolysosomal networkneurotrophin signalingRab5‐ASOsynaptic proteinstau phosphorylation

Identifiers

PMID40339155
PMCPMC12058459

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.