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

Abstract

Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, becauseis 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 compoundthat was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment withincreased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human-expressing model with hallmark amyloid-β pathology.