Chapter 24: Targeting ApoE in Alzheimer's Disease: Liver X Receptor Agonists as Potential Therapeutics Check Access

According to the amyloid hypothesis, increased production or decreased clearance of a neurotoxic peptide, Aβ, initiates a molecular cascade leading to neurodegeneration and cognitive decline. The major gene associated with Alzheimer's disease (AD) is the ε4 isoform of apoE. ApoE is a cholesterol transport protein. Patients expressing apoE4 have an earlier age at onset and a greater Aβ burden. Multiple genetic and pharmacological studies have suggested that apoE can facilitate Aβ clearance and degradation. It has recently been demonstrated that the apoE4 mutation is associated with low apoE protein levels which correlates with increased Aβ burden. Multiple groups have hypothesized that increasing apoE expression may be an effective strategy for treating AD. LXRα and LXRβ are nuclear hormone receptors known to regulate genes involved in cholesterol homeostasis, including apoE, and are therefore attractive pharmacological targets for AD. First generation non-steroidal LXR agonists have been shown to increase brain apoE levels, reduce Aβ load, improve behavioral deficits and reduce neuroinflammation in multiple animal models of Alzheimer's disease. Unfortunately, no LXR compound has yet progressed into late stage clinical trials due to the ability of LXRα to promote mechanism-based liver toxicity. This chapter will review the rationale for targeting LXRs in AD and highlight recent advances in developing LXR modulator compounds with reduced toxicity.