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Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer’s Disease and Type 2 Diabetes

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posted on 2023-02-22, 23:12 authored by Manel Ben Aissa, Cutler T Lewandowski, Kiira M Ratia, Sue H Lee, Brian LaydenBrian Layden, Mary LaduMary Ladu, Gregory RJ Thatcher
Selective liver X receptor (LXR) agonists have been extensively pursued as therapeutics for Alzheimer's disease and related dementia (ADRD) and, for comorbidities such as type 2 diabetes (T2D) and cerebrovascular disease (CVD), disorders with underlying impaired insulin signaling, glucose metabolism, and cholesterol mobilization. The failure of the LXR-focused approach led us to pursue a novel strategy to discover nonlipogenic ATP-binding cassette transporter A1 (ABCA1) inducers (NLAIs): screening for ABCA1-luciferase activation in astrocytoma cells and counterscreening against lipogenic gene upregulation in hepatocarcinoma cells. Beneficial effects of LXRβ agonists mediated by ABCA1 include the following: control of cholesterol and phospholipid efflux to lipid-poor apolipoproteins forming beneficial peripheral HDL and HDL-like particles in the brain and attenuation of inflammation. While rare, ABCA1 variants reduce plasma HDL and correlate with an increased risk of ADRD and CVD. In secondary assays, NLAI hits enhanced cholesterol mobilization and positively impacted in vitro biomarkers associated with insulin signaling, inflammatory response, and biogenic properties. In vivo target engagement was demonstrated after oral administration of NLAIs in (i) mice fed a high-fat diet, a model for obesity-linked T2D, (ii) mice administered LPS, and (iii) mice with accelerated oxidative stress. The lack of adverse effects on lipogenesis and positive effects on multiple biomarkers associated with T2D and ADRD supports this novel phenotypic approach to NLAIs as a platform for T2D and ADRD drug discovery.


Center for Clinical and Translational Science Award U54 | Funder: National Institutes of Health (National Center for Advancing Translational Sciences) | Grant ID: UL1TR002003

The Function and Regulation of the Novel Pregnancy-Specific Hexokinase HKDC1 | Funder: National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) | Grant ID: R01DK104927

Potential ApoE Isoform-Specific Detrimental Effects of RXR Agonists in Alzheimer' | Funder: National Institute on Aging | Grant ID: R21AG044682

Training Program in the Biology and Translational Research on Alzheimer's Disease and Related Dementias | Funder: National Institutes of Health (National Institute on Aging) | Grant ID: T32AG057468



Aissa, M. B., Lewandowski, C. T., Ratia, K. M., Lee, S. H., Layden, B. T., LaDu, M. J.Thatcher, G. R. J. (2021). Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer’s Disease and Type 2 Diabetes. ACS Pharmacology & Translational Science, 4(1), 143-154.


American Chemical Society (ACS)