Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer's Disease Validated in a Mouse Model Expressing Human APOE3/APOE4 .
Ganga Reddy VelmaMegan S LahamCutler LewandowskiAna C Valencia-OlveraDeebika BaluAnnabelle MooreMartha Ackerman-BerrierPavel RychetskyChristopher PentonSoumya Reddy MuskuAnandhan AnnaduraiMaha Ibrahim SulaimanNina MaGregory R J ThatcherPublished in: Journal of medicinal chemistry (2024)
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.
Keyphrases
- cognitive decline
- endothelial cells
- high fat diet
- mild cognitive impairment
- induced pluripotent stem cells
- mouse model
- pluripotent stem cells
- type diabetes
- small molecule
- poor prognosis
- multiple sclerosis
- early onset
- white matter
- metabolic syndrome
- wild type
- genome wide
- blood brain barrier
- combination therapy
- high density