Alzheimer's disease (AD) is a common neurodegenerative disease characterized by the accumulation of extracellular plaques and intracellular tangles. Recent studies support the hypothesis that the accumulation of amyloid beta (Aβ) peptide within the brain arises from an imbalance of the production and clearance of Aβ. In rare genetic forms of AD, this imbalance is often caused by increased production of Aβ. However, recent evidence indicates that, in the majority of cases of AD, Aβ clearance is impaired. Apolipoprotein E (ApoE), the dominant cholesterol and lipid carrier in the brain, is critical for Aβ catabolism. The isoform of ApoE and its degree of lipidation critically regulate the efficiency of Aβ clearance. Studies in preclinical models of AD have demonstrated that coordinately increasing levels of ApoE and its lipid transporter, ABCA1, increases the clearance of Aβ, suggesting that this pathway may be a potential therapeutic target for AD.

Nuclear receptors have generated substantial interest in the past decade as potential therapeutic targets for the treatment of neurodegenerative disorders. Despite years of effort, effective treatments for progressive neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and ALS remain elusive, making non-classical drug targets such as nuclear receptors an attractive alternative. A substantial literature in mouse models of disease and several clinical trials have investigated the role of nuclear receptors in various neurodegenerative disorders, most prominently AD. These studies have met with mixed results, yet the majority of studies in mouse models report positive outcomes. The mechanisms by which nuclear receptor agonists affect disease pathology remain unclear. Deciphering the complex signaling underlying nuclear receptor action in neurodegenerative diseases is essential for understanding this variability in preclinical studies, and for the successful translation of nuclear receptor agonists into clinical therapies.

Background:In the brain, the type II nuclear receptors LXR and PPAR␥ control cholesterol efflux and inflammation, key processes in Alzheimer disease pathology. Results: Combining the LXR and PPAR␥ agonists decreases the levels of A␤ and inflammation, resulting in improved cognition. Conclusion:The LXR and PPAR␥ agonists complement each other, possibly by modulating microglial function. Significance: Targeting multiple nuclear receptors expands the therapeutic opportunities for AD treatment.