Evidence map›Paper›PMID 40269061›Full record

ArticleScientific reports2025

Discovery of an ApoE4-targeted small-molecule SirT1 enhancer for the treatment of Alzheimer's disease.

Jesus Campagna, Sujyoti Chandra, Bruce Teter, Whitaker Cohn, Johnny Pham, Young-Sug Kim, Barbara Jagodzinska, Kanagasabai Vadivel, Parvez Alam, Tina Bilousova and 12 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Scientific reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing 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

2 citing papers in PubMed.

  1. Review
  2. NADAlzheimer's & dementia : the journal of the Alzheimer's Association · 2026
    Review
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

22 authors.

Jesus Campagna *The Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Sujyoti Chandra *The Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Bruce TeterThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Whitaker CohnThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Johnny PhamDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, 650 Charles E. Young Drive, Los Angeles, CA, 90095, USA.
Young-Sug KimDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, 650 Charles E. Young Drive, Los Angeles, CA, 90095, USA.
Barbara JagodzinskaThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Kanagasabai VadivelThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Parvez AlamThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Tina BilousovaThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Malaney YoungThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Chris EliasThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Juan MarcucciThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Ilinca FlacauThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Ainsley JackmanThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Samar PadderThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Dongwook WiThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Chunni ZhuThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Patricia SpilmanThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Michael E JungDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, 650 Charles E. Young Drive, Los Angeles, CA, 90095, USA.
Dale E BredesenThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
Varghese JohnThe Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA. vjohn@mednet.ucla.edu.

Funding

ApoE4-targeted therapeutics that normalize SirT1R01AG051386 · NIA · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI JOHN, VARGHESE · 2015 to 2019
$3.0M
NIA NIH HHS R01 AG051386NIH HHS AG051386-01
6 · The paper itself

Abstract

Decreased expression of sirtuin 1 (SirT1) has been implicated in Alzheimer's disease (AD), and as we previously reported, is related to transcriptional repression by the major risk factor for sporadic AD, apolipoprotein E4 (ApoE4). Herein we describe the discovery of an orally brain-permeable small-molecule, DDL-218, that enhanced SirT1 in ApoE4-expressing neuronal cells and a murine AD model. DDL-218 increased the transcription factor NFYb resulting in upregulation of PRMT5. Mechanistic and modeling studies show that binding of ApoE4 to the SirT1 gene promoter can be displaced by PRMT5 leading to increased SirT1 transcription. DDL-218 treatment elicited improvement in memory in the AD model, suggesting that DDL-218 enhancement of neurotrophic SirT1 in the brain has potential to modulate neuronal activity that may clinically provide an improvement in cognitive function and complement the current anti-Aβ antibody monotherapy. Our findings support further development of DDL-218 as a novel ApoE4-targeted therapeutic candidate for AD.

Indexed as

Alzheimer DiseaseApolipoprotein E4Sirtuin 1AnimalsDisease Models, AnimalHumansMiceMice, TransgenicNeuronsPromoter Regions, GeneticApolipoprotein E4Sirtuin 1Apolipoprotein E4DDL-218MemoryNFYbPRMT5SirT1SirT1 enhancerSirtuin 1

Identifiers

PMID40269061
PMCPMC12019328

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.