2. Academic Validation
  3. Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer's Disease Validated in a Mouse Model Expressing Human APOE3/APOE4

Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer's Disease Validated in a Mouse Model Expressing Human APOE3/APOE4

  • J Med Chem. 2024 Sep 12;67(17):15061-15079. doi: 10.1021/acs.jmedchem.4c00733.
Ganga Reddy Velma 1,  Megan S Laham 2,  Cutler Lewandowski 3,  Ana C Valencia-Olvera 4,  Deebika Balu 4,  Annabelle Moore 4,  Martha Ackerman-Berrier 1,  Pavel Rychetsky 1,  Christopher Penton 1,  Soumya Reddy Musku 1,  Anandhan Annadurai 1,  Maha Ibrahim Sulaiman 1,  Nina Ma 1,  Gregory R J Thatcher 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacology & Toxicology, R Ken Coit College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States.
  • 2 Department of Chemistry & Biochemistry, Colleges of Science & Medicine, University of Arizona, Tucson, Arizona 85721, United States.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
  • 4 Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
PMID: 39191400 DOI: 10.1021/acs.jmedchem.4c00733
Abstract

Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because APOE4 is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport Cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane Cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound 39 that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with 39 increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human APOE-expressing model with hallmark Amyloid-β pathology.

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