Role for the liver X receptor agonist 22-ketositosterol in preventing disease progression in an Alzheimer's disease mouse model

Abstract

Background and purpose: Liver X receptors (LXRs) are promising therapeutic targets for alleviating Alzheimer's disease (AD) symptoms. We assessed the impact of the semi-synthetic LXR agonist 22-ketositosterol on disease progression in an AD mouse model.

Experimental approach: From 5.5 months of age, APPswePS1ΔE9 (AD) mice and wild-type (WT) littermates received a regular or 22-ketositosterol-supplemented diet (0.017% w/w). Cognition was assessed with object location and recognition tasks and a spontaneous alternation Y-maze test. Amyloid β was quantified using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA), microglia (Iba1, CD68) and astrocyte (GFAP) markers using IHC. Sterols were determined in food, serum, liver and cerebellum.

Key results: 22-Ketositosterol activated both liver X receptors-α and -β and promoted cholesterol efflux in cell cultures. Diet supplementation with 22-ketositosterol prevented a decline in the performance of APPswePS1ΔE9 mice in the object location task but not in the other two tasks. Without affecting amyloid β deposition, 22-ketositosterol decreased microglia (Iba1, CD68) and astrocyte (GFAP) markers in the cortex and hippocampus of APPswePS1ΔE9, suggesting potential anti-inflammatory effects. No lipid accumulation was detected in the liver or serum upon 22-ketositosterol supplementation.

Conclusions and implications: Diet supplementation with 22-ketositosterol prevented the decline in spatial memory of APPswePS1ΔE9 mice. Our data suggest therapeutic benefits of 22-ketositosterol possibly by enhancing cholesterol efflux and mitigating inflammatory responses, without inducing hepatosteatosis or hypertriglyceridemia.

Keywords: Alzheimer's disease; cholesterol metabolism; liver X receptors; oxysterols.