PXD060379

PXD060379 is an original dataset announced via ProteomeXchange.

Title	Discovery of an ApoE4-Targeted Small-Molecule SirT1 Enhancer for the Treatment of Alzheimer’s Disease
Description	Herein we describe the discovery of an orally brain-22 permeable small-molecule, DDL-218, that enhanced SirT1 in ApoE4-expressing neuronal cells 23 and a murine AD model. DDL-218 increased the transcription factor NFYb resulting in 24 upregulation of PRMT5. Mechanistic and modeling studies show that binding of ApoE4 to the 25 SirT1 gene promoter can be displaced by PRMT5 leading to increased SirT1 transcription. DDL-26 218 treatment elicited improvement in memory in the AD model, suggesting that DDL-218 27 enhancement of neurotrophic SirT1 in the brain has potential to modulate neuronal activity that 28 may clinically provide an improvement in cognitive function and complement the current anti-29 Aβ antibody monotherapy. Our findings support further development of DDL-218 as a novel 30 ApoE4-targeted therapeutic candidate for AD.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-07_06:59:06.732.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD060379
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Jesus Campagna
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-30 13:14:10	ID requested
⏵ 1	2025-05-07 06:59:07	announced

10.1038/s41598-025-96131-2;

Campagna J, Chandra S, Teter B, Cohn W, Pham J, Kim YS, Jagodzinska B, Vadivel K, Alam P, Bilousova T, Young M, Elias C, Marcucci J, Flacau I, Jackman A, Padder S, Wi D, Zhu C, Spilman P, Jung ME, Bredesen DE, John V, Discovery of an ApoE4-targeted small-molecule SirT1 enhancer for the treatment of Alzheimer's disease. Sci Rep, 15(1):14028(2025) [pubmed]

10.6019/PXD060379;

submitter keyword: sirtuin 1, PRMT5, NFYb, SirT1, SirT1 enhancer, memory,apolipoprotein E4

Varghese John
contact affiliation	The Drug Discovery Lab, Mary S. Easton Center for Alzheimer’s Disease Research, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, University of California Los Angeles, Los Angeles, CA 90095, USA
contact email	vjohn@mednet.ucla.edu
lab head
Jesus Campagna
contact affiliation	UCLA
contact email	jcampagna@mednet.ucla.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/05/PXD060379

PRIDE project URI

• PRIDE
  1. PXD060379
     1. Label: PRIDE project
     2. Name: Discovery of an ApoE4-Targeted Small-Molecule SirT1 Enhancer for the Treatment of Alzheimer’s Disease