Riddell et al. reported that TO-901317, a liver X receptor (LXR) agonist, at brain concentrations of 5 μMol/l reduced Aβ42 levels in the Tg2576 mouse model and reversed the contextual memory deficit in these mice. They came to the conclusion that TO-901317 at a dosage well above the ED50 for LXR does not directly interfere with APP processing and tentatively attributed the activity to an ApoE-mediated mechanism. An opposite effect was observed in vitro; Czech et al. demonstrated recently that TO-901317 interacts with γ-secretase in a cell-free assay to alter the production of different Aβ peptides. TO-901317 was found to be an inverse modulator of γ-secretase and displayed activity at concentrations close to the ED50 for LXR agonism.

This discrepancy is not addressed in the current paper, and again the LXR agonist was applied at high concentrations while TO-901317 brain levels were not determined.

References:
Riddell DR, Zhou H, Comery TA, Kouranova E, Lo CF, Warwick HK, Ring RH, Kirksey Y, Aschmies S, Xu J, Kubek K, Hirst WD, Gonzales C, Chen Y, Murphy E, Leonard S, Vasylyev D, Oganesian A, Martone RL, Pangalos MN, Reinhart PH, Jacobsen JS. The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer's disease. Mol Cell Neurosci. 2007 Apr 1;34(4):621-8. Abstract

Narlawar R, Baumann K, Czech C, Schmidt B. Conversion of the LXR-agonist TO-901317--from inverse to normal modulation of gamma-secretase by addition of a carboxylic acid and a lipophilic anchor. Bioorg Med Chem Lett. 2007 Oct 1;17(19):5428-31. Abstract

View all comments by Boris Schmidt