Design and Development of Novel LXRβ Agonists for Alzheimer’s Disease

Abstract

A progressive neurodegenerative disease, Alzheimer's disease (AD) is identified by the buildup of insoluble protein aggregates, such as Tau and amyloid beta. Amyloid beta (Aβ) and Tau protein processing genetic predispositions are highly correlated with the prevalence of disease. But AD's pathological features can exist separately from one another. Furthermore, individuals who are genetically predisposed to AD may never get it, suggesting that lifestyle decisions and epigenetic factors have a big impact on the onset and course of the disease.

Apolipoprotein E (ApoE) mutations are the single most important genetic risk factor for AD development; the most prevalent ApoE mutations produce three distinct phenotypes: ApoE2, ApoE3, and ApoE4. Commonly known as neutral alleles, ApoE2 and ApoE3 have been shown in some studies to be protective. The ApoE4 allele is the most significant risk factor for the development of AD because it causes the most drastic alteration in cholesterol transport in these patients, which leads to a higher rate of neurovascular dysfunction and blood-brain barrier (BBB) degradation.

Lipids are transported by ApoE as protein complexes, for example, High-Density Lipoprotein (HDL), Low-Density Lipoprotein (LDL), Very Low-Density Lipoprotein (VLDL), and others, which differ in size, density, and function. Astrocytes, a non-neuronal cell type that performs a variety of regulatory tasks, such as maintaining the blood-brain barrier, forming myelin, controlling nutrition, and eliminating toxic metabolites like Tau and Aβ, are the cells in the brain that express APOE the most. Patients with atherosclerotic plaques are the target of current therapeutic applications that modulate ApoE. These applications encourage the removal of lipids from peripheral tissues and return them to the liver for further elimination. This process, called reverse cholesterol transport (RCT), raises HDL cholesterol while lowering LDL cholesterol.

Liver X receptors (LXRs) are attractive targets in the paradigm of RCT-mediated therapeutic benefit because they can directly alter ApoE regulation and improve related deficits in AD patients. Through RCT mechanisms, LXRs transcriptionally regulate a number of genes linked to lipid metabolism, energy regulation, and cholesterol clearance. Systemic toxicities like steatosis and neutropenia have prevented LXR-specific agonists from receiving FDA approval, despite their promising results in various transgenic animal models of atherosclerosis and AD. The challenge of achieving therapeutic specificity among the variability of LXR isoforms and function to stop undesired off-target activity in healthy tissue types exacerbates this problem.

Therefore, in order to obtain structure-activity relationships and mechanical details that identify novel ligands with improved therapeutic efficacy, our computational design for novel LXR compounds has focused on profiling selective ligand interactions between the two isoforms of these receptors.