Remembering your A, B, C's: Alzheimer's disease and ABCA1

Abstract

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.

Keywords: Alzheimer's disease; Cardiovascular disease; Cholesterol; Drug discovery; Liver X receptor; Nuclear hormone receptor; Type 2 diabetes.

Graphical abstract

Figure 1

Proposed beneficial roles of ABCA1 in AD, ADRD, and comorbidities. ABCA1 mediates cellular cholesterol efflux, such that increased ABCA1 expression would be expected to produce several direct and indirect beneficial effects via an enhancement of efflux activity. These effects would provide therapeutic efficacy both in the brain and in peripheral tissues.

Figure 2

Brain cholesterol transport by ABCA1 and APOE. ABCA1 transports cholesterol out of cells to promote lipidation of secreted APOE to form lipoprotein particles (1), which are either internalized by cholesterol-deficient cells or transported across the BBB to maintain brain cholesterol homeostasis (2). Poorly lipidated APOE4 (compared to APOE3 or APOE2) is prone to degradation, disrupting this homeostasis and contributing to AD pathology (3). Internal CNS control of cholesterol homeostasis is regulated by neuronal expression of CYP46A1 enzyme, which converts excess cholesterol to 24-hydroxycholesterol (4). This form can cross the BBB (unlike cholesterol itself), and it acts as an endogenous agonist of LXR to promote expression of the cholesterol transport machinery. This endogenous control mechanism is disrupted in AD, predisposing brain cells to cholesterol overload. Small molecule ABCA1 inducers may elicit therapeutic effects against AD by boosting cholesterol transport, particularly via increased APOE lipidation in APOE4 carriers.

Figure 3

APOE, ABCA1, and inflammation. (A) Neuronal NMDA stimulation increased fatty acid and triglycerides (TGs) leading to decreased mitochondrial respiration, lipid peroxidation, and increased reactive oxygen species (ROS); in turn leading to lipotoxicity and neuronal death. Transport of fatty acids, TGs and lipid peroxidation products (LPPs) from neurons to astrocytes by lipidated APOE rescued neurons by lysosomal catabolism of fatty acids, storage in lipid droplets, and use for mitochondrial oxidative phosphorylation; which was accompanied by transcriptional upregulation of LXR and NRF2 target genes. (B) APOE4 neurons showed 36% lower APOE, reduced neurite branching, elevated fatty acids and TGs, and decreased mitochondrial function and glucose metabolism. APOE4 astrocytes were less efficient at transporting lipids and fatty acids from neurons and at fatty acid catabolism and energy conversion, containing fragmented mitochondria and elevated TGs.

Figure 4

NHR and ligand structures (H12 orange; H3 yellow; H11 blue; ligand red; coregulator silver). (A) ERα in “antagonist conformation” with SERM raloxifene displacing H12 (PDB 2JFA). (B) ERα in “agonist conformation” with TTC-352 inducing closure, stabilizing H12, and binding the coactivator NCOA2 (PDB 7JHD). (C) Merck Comp9 LXR agonist (LXRβ: PDB 5HJP). (D) LXR “inverse agonist” (LXRβ: PDB 6K9M). (E) GSK3986 (LXRα; PDB 2ACL with NCOA1 bound): showing similarity with ER agonist conformation forming AF-2; and similar binding poses with both LXR isoforms and with agonists and inverse agonists. (F) LXRβ:RXRα heterodimer bound to DR-4 DNA element including LBDs, coregulator, and DNA-binding domains (4NQA): although containing more components of the transcriptional complex, intrinsically disordered N-terminal domains (containing AF-1) are absent. Tissue selectivity of NR ligands is widely believed to result from cell-specific coregulator expression; however, the ligand is dominant as the linchpin in allosteric communication between coregulators and DNA.