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

Abstract

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.

LXR Regulation of Brain Cholesterol: From Development to Disease

“…In experimental models, synthetic LXR ligands increase plasma cholesterol levels and cause hypertriglyceridemia [83]. New compounds with better tissue specificity or LXR isoform targeting could allow for better translatability of LXR agonists, and elucidation of the mechanisms by which LXRs modulate neuronal survival and neuroinflammation can further inform the search for targeted drugs.…”

Transcriptional control of microglia phenotypes in health and disease

“…However, the role of PPARs in microglia and neuroinflammation is still poorly understood. A rapidly growing number of studies have investigated the role of PPARγ agonists in neurodegenerative conditions such as AD, PD, HD, and amyotrophic lateral sclerosis, but these findings have not conclusively shown a protective effect (113). However, in AD mice, a PPARγ agonist did…”

Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

“…Nonetheless, there are numerous animal studies evaluating the therapeutic potential of compounds that increase brain apoE levels [99–115]. Transcription of APOE is positively regulated by nuclear receptors, retinoid X receptors (RXRs) and liver X receptors (LXRs), which form heterodimers [116].…”

“…Treatment with a PPARγ agonist, rosiglitazone, rescued memory deficits and reduced amyloid and tau pathology in amyloid mouse model without increasing brain apoE levels [114]. Another PPARγ agonist, pioglitazone, increased apoE, decreased Aβ, and improved cognition in an amyloid mouse model with a synergistic effect observed upon co-treatment with the LXR agonist GW3965 [115]. In addition, all-trans retinoic acid (RA), 9-cis RA and 13-cis RA have been identified as effective modulators of apoE production through RXR and RAR in astrocytes [127].…”