Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid ß Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice.

Alzheimer disease (AD) is characterized by the extracellular accumulation of amyloid ß (Aß), which is accompanied by a robust inflammatory response in the brain. Both of these pathogenic processes are regulated by nuclear receptors, including the liver X receptors (LXRs) and peroxisome-proliferator receptor γ (PPARγ). Agonists of LXRs have been demonstrated previously to reduce Aß levels and improve cognitive deficits in AD mouse models by inducing the transcription and lipidation of apolipoprotein E (apoE). Agonists targeting PPARγ reduce the microglial expression of proinflammatory genes and have also been shown to modulate apoE expression. Here we investigate whether a combination therapy with both LXR and PPARγ agonists results in increased benefits in an AD mouse model. We found that the LXR agonist GW3965 and the PPARγ agonist pioglitazone were individually able to increase the levels of apoE and related genes, decrease the expression of proinflammatory genes, and facilitate Aß decreases in the hippocampus. Combined treatment with both agonists provoked a further increase in the expression of apoE and a decrease in the soluble and deposited forms of Aß. The decrease in plaques was associated with increased colocalization between microglia and plaques. In addition, the PPARγ agonist in the combined treatment paradigm was able to counteract the elevation in plasma triglycerides that is a side effect of LXR agonist treatment. These results suggest that combined LXR/PPARγ agonist treatment merits further investigation for the treatment of AD.

Nuclear receptors in neurodegenerative diseases.

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.

Evidence for impaired amyloid ß clearance in Alzheimer's disease.

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 (Aß) peptide within the brain arises from an imbalance of the production and clearance of Aß. In rare genetic forms of AD, this imbalance is often caused by increased production of Aß. However, recent evidence indicates that, in the majority of cases of AD, Aß clearance is impaired. Apolipoprotein E (ApoE), the dominant cholesterol and lipid carrier in the brain, is critical for Aß catabolism. The isoform of ApoE and its degree of lipidation critically regulate the efficiency of Aß clearance. Studies in preclinical models of AD have demonstrated that coordinately increasing levels of ApoE and its lipid transporter, ABCA1, increases the clearance of Aß, suggesting that this pathway may be a potential therapeutic target for AD.