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Drug Development.

Samar Padder1, Jesus J Campagna1, Sujyoti Chandra1

  • 1University of California, Los Angeles (UCLA), Los Angeles, CA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 25, 2025
PubMed
Summary
This summary is machine-generated.

A new drug, DDL-218, enhances neuroprotective Sirtuin 1 (SirT1) levels by counteracting the effects of apolipoprotein E4 (ApoE4). This Alzheimer's disease (AD) therapy candidate improved memory in preclinical models.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Genetics

Background:

  • Alzheimer's disease (AD) involves amyloid plaques and tau tangles.
  • Apolipoprotein E4 (ApoE4) is a major genetic risk factor for sporadic AD.
  • ApoE4 represses Sirtuin 1 (SirT1), a crucial neuroprotective protein, exacerbating AD progression.

Purpose of the Study:

  • Discover and preclinically evaluate DDL-218, a small-molecule SirT1 enhancer.
  • Target ApoE4 to reverse its repressive effects on SirT1 expression.
  • Assess DDL-218's therapeutic potential for Alzheimer's disease.

Main Methods:

  • High-throughput screening identified SirT1 enhancer candidates.
  • Medicinal chemistry and in silico modeling optimized lead compounds.
  • In vitro and in vivo studies in ApoE4-expressing neuronal cells and AD mouse models were performed.
  • Mechanisms were investigated using proteomics, chromatin immunoprecipitation, and qRT-PCR.

Main Results:

  • DDL-218 increased SirT1 protein and mRNA by upregulating NFYB and PRMT5.
  • Drug treatment displaced ApoE4 from the SirT1 promoter, boosting SirT1 expression.
  • DDL-218 improved memory in AD mouse models and enhanced brain SirT1, NFYB, and PRMT5 mRNA.
  • Proteomics indicated upregulation of neuronal function proteins like PTprn2; DDL-218 demonstrated brain penetration and safety.

Conclusions:

  • DDL-218 effectively enhances SirT1 by counteracting ApoE4, showing therapeutic promise for AD.
  • The compound improved cognition and neural pathways in preclinical AD models.
  • Further research is warranted to establish DDL-218's targets, mechanism, and efficacy in diverse ApoE4-related AD models.