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

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

  • Sci Rep. 2025 Apr 23;15(1):14028. doi: 10.1038/s41598-025-96131-2.
Jesus Campagna # 1,  Sujyoti Chandra # 1,  Bruce Teter 1,  Whitaker Cohn 1,  Johnny Pham 2,  Young-Sug Kim 2,  Barbara Jagodzinska 1,  Kanagasabai Vadivel 1,  Parvez Alam 1,  Tina Bilousova 1,  Malaney Young 1,  Chris Elias 1,  Juan Marcucci 1,  Ilinca Flacau 1,  Ainsley Jackman 1,  Samar Padder 1,  Dongwook Wi 1,  Chunni Zhu 1,  Patricia Spilman 1,  Michael E Jung 2,  Dale E Bredesen 1,  Varghese John 3
Affiliations

Affiliations

  • 1 The Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
  • 2 Department of Molecular and Medical Pharmacology, University of California Los Angeles, 650 Charles E. Young Drive, Los Angeles, CA, 90095, USA.
  • 3 The Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, Los Angeles, CA, 90095, USA. vjohn@mednet.ucla.edu.
  • # Contributed equally.
PMID: 40269061 DOI: 10.1038/s41598-025-96131-2
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.

Keywords

Apolipoprotein E4; DDL-218; Memory; NFYb; PRMT5; SirT1; SirT1 enhancer; Sirtuin 1.

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