Discovery of an ApoE4-targeted small-molecule SirT1 enhancer for the treatment of Alzheimer’s disease
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.
Authors
- Kanagasabai Vadivel (ORCID: https://orcid.org/0000-0003-3777-9540)
- Chris Jean Elias
- Chunni Zhu
- Parvez Alam (ORCID: https://orcid.org/0000-0002-4484-8340)
- Malaney C. Young (ORCID: https://orcid.org/0000-0001-5857-2851)
- Jesus Campagna
- Bruce Teter (ORCID: https://orcid.org/0000-0002-8337-4491)
- Varghese John (ORCID: https://orcid.org/0000-0001-7675-2426)
- Barbara Jagodzinska (ORCID: https://orcid.org/0009-0006-5706-3725)
- Sujyoti Chandra (ORCID: https://orcid.org/0000-0001-5105-9801)
- Tina Bilousova (ORCID: https://orcid.org/0000-0002-4855-3953)
- Michael E. Jung (ORCID: https://orcid.org/0000-0003-1290-8588)
- Jared Marcucci
- Yong‐Mi Kim (ORCID: https://orcid.org/0000-0003-3793-6438)
- Whitaker Cohn (ORCID: https://orcid.org/0000-0001-9198-8904)
- Dongwook Wi
- Patricia Spilman (ORCID: https://orcid.org/0000-0003-1999-1169)
- Dale E. Bredesen (ORCID: https://orcid.org/0000-0002-9395-8263)
- Johnny D. Pham
- A.L. Jackman
- Ilinca Flacau
- Samar Padder
Institutions
- Los Angeles Medical Center (US)
- Drug Discovery Laboratory (Norway) (NO)
- Charles R. Drew University of Medicine and Science (US)
Publication Details
- Journal
- Scientific Reports
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1038/s41598-025-96131-2
- Citations
- 2
- Primary Topic
- Endoplasmic Reticulum Stress and Disease
- Type
- article
- Field-Weighted Citation Impact
- 2.30
Funders
- National Institutes of Health