Cutler T. Lewandowski, Megan S. Laham, Gregory R. J. Thatcher. Remembering your A, B, C's: Alzheimer's disease and ABCA1[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 995-1018

Remembering your A, B, C's: Alzheimer's disease and ABCA1
Cutler T. Lewandowskia, Megan S. Lahamb, Gregory R. J. Thatcherb
a. Department of Pharmaceutical Sciences, University of Illinois College of Pharmacy, Chicago, IL 60612, USA;
b. Department of Pharmacology and Toxicology, University of Arizona College of Pharmacy, Tucson, AZ 85721, USA
The function of ATP binding cassette protein A1 (ABCA1) is central to cholesterol mobilization. Reduced ABCA1 expression or activity is implicated in Alzheimer's disease (AD) and other disorders. Therapeutic approaches to boost ABCA1 activity have yet to be translated successfully to the clinic. The risk factors for AD development and progression, including comorbid disorders such as type 2 diabetes and cardiovascular disease, highlight the intersection of cholesterol transport and inflammation. Upregulation of ABCA1 can positively impact APOE lipidation, insulin sensitivity, peripheral vascular and blood-brain barrier integrity, and anti-inflammatory signaling. Various strategies towards ABCA1-boosting compounds have been described, with a bias toward nuclear hormone receptor (NHR) agonists. These agonists display beneficial preclinical effects; however, important side effects have limited development. In particular, ligands that bind liver X receptor (LXR), the primary NHR that controls ABCA1 expression, have shown positive effects in AD mouse models; however, lipogenesis and unwanted increases in triglyceride production are often observed. The longstanding approach, focusing on LXRβ vs. LXRα selectivity, is over-simplistic and has failed. Novel approaches such as phenotypic screening may lead to small molecule NHR modulators that elevate ABCA1 function without inducing lipogenesis and are clinically translatable.
Key words:    Alzheimer's disease    Cardiovascular disease    Cholesterol    Drug discovery    Liver X receptor    Nuclear hormone receptor    Type 2 diabetes   
Received: 2021-11-12     Revised: 2021-12-27
DOI: 10.1016/j.apsb.2022.01.011
Funds: Cutler T. Lewandowski was supported by NIH T32AG57468 (USA) and American Heart Association 20PRE35150022 (USA) and is a trainee in the University of Illinois Medical Scientist Training Program (USA). Additional funding was provided through the UICentre for Drug Discovery as supported by the National Center for Advancing Translational Sciences, NIH UL1TR002003 (USA).
Corresponding author: Gregory R. J. Thatcher,
Author description:
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Cutler T. Lewandowski
Megan S. Laham
Gregory R. J. Thatcher

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