| dc.description.abstract | Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of insoluble protein aggregates, i.e., amyloid beta and Tau. Genetic predispositions in amyloid beta (A) and Tau protein processing correlate strongly with disease prevalence. However, pathological hallmarks of AD can exist independently of each other. Additionally, patients with a genetic predisposition may never develop AD, indicating that epigenetic influences and lifestyle choices significantly impact disease initiation and progression.
Mutations in Apolipoprotein E (APOE) constitute the single most significant genetic risk factor for developing AD—the most commonly occurring mutations for APOE result in three different phenotypes: APOE2, APOE3, and APOE4. APOE2 and APOE3 are frequently referred to as neutral alleles, with the former being protective in certain studies. It is the APOE4 allele that poses the most significant risk for AD development, as cholesterol transport is most dramatically altered in these patients, resulting in an increased rate of blood-brain barrier (BBB) degradation and neurovascular dysfunction.
APOE transports lipids in the form of protein complexes that vary in size, density, and function, i.e., HDL, LDL, VLDL, etc. APOE is most abundantly expressed within the brain by astrocytes, a non-neuronal cell type responsible for many regulatory functions, including maintenance of the BBB, formation of myelin, regulation of nutrients, and removal of harmful metabolites, e.g., A and Tau. Current therapeutic applications that modulate APOE target patients with atherosclerotic plaques and promote the removal of lipids from the peripheral tissues, transporting them back to the liver for subsequent elimination. In so doing, HDL (“healthy” cholesterol) is increased, and LDL (“bad” cholesterol) is lowered in a process known as reverse cholesterol transport (RCT).
In the paradigm of RCT-mediated therapeutic benefit, Peroxisome-proliferator-activated receptors (PPARs) and liver-X receptors (LXRs) are enticing targets, as they can directly modulate APOE regulation to improve associated deficits in patients with AD. PPAR/LXRs transcriptionally regulate various genes related to energy regulation, lipid metabolism, and cholesterol clearance through RCT mechanisms. While PPAR and LXR-specific agonists have shown promise in different transgenic animal models with atherosclerosis and AD, they perform poorly in human clinical trials and have failed to achieve FDA approval due to systemic toxicities such as steatosis, neutropenia, edema, and cardiotoxicity. Complicating this issue is the difficulty of attaining therapeutic specificity amongst PPAR/LXR isoform variability and function to prevent undesirable off-target activity in healthy tissue types.
Therefore, our computational design for novel PPAR/LXR compounds has centered around profiling selective ligand interactions across all isoforms of these receptors to gather surface activity relationships and mechanical details that identify novel ligands with improved therapeutic efficacy. | en_US |
