Discovery of an ApoE4‐Targeted Small‐Molecule SirT1 Enhancer for the Treatment of Alzheimer’s Disease
DDL-218 successfully enhanced SirT1 expression by counteracting ApoE4's repressive effects, demonstrating potential as a therapeutic strategy for AD. DDL-218 improved memory and key neural pathways, showing promise in preclinical models. The observed cognitive improvements in the mouse model support further investigation of DDL-218 as a novel treatment for Alzheimer's, targeting ApoE4-driven disease mechanisms. Future studies will establish protein targets of DDL-218 and clarify its mechanism in increasing NFYB mRNA levels. Additionally, we will evaluate its safety profile and efficacy in other ApoE4-expressing in vivo models.
Authors
- Chris Jean Elias
- Mohammad Parvez Alam (ORCID: https://orcid.org/0000-0002-3519-5413)
- Chunni Zhu
- 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)
- Whitaker Cohn (ORCID: https://orcid.org/0000-0001-9198-8904)
- Dongwook Wi
- Patricia Spilman (ORCID: https://orcid.org/0000-0003-1999-1169)
- Youngsuk Song
- Dale E. Bredesen (ORCID: https://orcid.org/0000-0002-9395-8263)
- Johnny D. Pham
- Ilinca Flacau
- Samar Padder
- Juan Marcucci
- Kanagasabai Vadivel
- Ainsley Jackman
Institutions
- University of California, Los Angeles (US)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1002/alz70859_101293
- Primary Topic
- Sirtuins and Resveratrol in Medicine
- Type
- article
- Field-Weighted Citation Impact
- 0.00