The LXR agonist TO901317 selectively lowers hippocampal A beta 42 and improves memory in the Tg2576 mouse model of Alzheimer's disease

Recent studies show that intracellular cholesterol levels can modulate the processing of amyloid precursor protein to A beta peptide. Moreover, cholesterol-rich apoE-containing lipoproteins may also promote A beta clearance. Agonists of the liver X receptor (LXR) transcriptionally induce genes involved in intracellular lipid efflux and transport, including apoE. Thus, LXR agonists have the potential to both inhibit APP processing and promote A beta clearance. Here we show that LXR agonist, TO901317, increased hippocampal ABCA1 and apoE and decreased A beta 42 levels in APP transgenic mice. TO901317 had no significant effects on levels of A beta 40, full length APP, or the APP processing products. Next, we examined the effects of TO901317 in the contextual fear conditioning paradigm; TO901317 completely reversed the contextual memory deficit in these mice. These data demonstrate that LXR agonists do not directly inhibit APP processing but rather facilitate the clearance of A beta 42 and may represent a novel therapeutic approach to Alzheimer's disease.