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J. Biol. Chem., Vol. 280, Issue 6, 4079-4088, February 11, 2005

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The Liver X Receptor Ligand T0901317 Decreases Amyloid Production in Vitro and in a Mouse Model of Alzheimer's Disease^*

Radosveta P. Koldamova¶, Iliya M. Lefterov||, Matthias Staufenbiel**, Darren Wolfe, Shaohua Huang, Joseph C. Glorioso, Michael Walter, Michael G. Roth¶¶, and John S. Lazo

From the Department of Pharmacology and the Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, ^**Novartis Institutes of BioMedical Research, CH-4002 Basel, Switzerland, the Institute of Clinical Chemistry and Laboratory Medicine and Institute of Arteriosclerosis Research at the University of Münster, 48149 Münster, Germany, and the ^¶¶Department of Biochemistry, University of Texas, Southwestern Medical Center, Dallas, Texas 75235

Recent studies indicate that oxysterols, which are ligands for the nuclear hormone liver X receptors (LXR), decrease amyloid (A) secretion in vitro. The effect was attributed primarily to the ATP-binding cassette transporter A1 (ABCA1) transcriptionally up-regulated by ligand-activated LXRs. We now examined the effect of the synthetic LXR ligand T0901317, which can be used in vivo, on A production in vitro and in APP23 transgenic mice. T0901317 applied to a variety of in vitro models, including immortalized fibroblasts from Tangier patients, and primary embryonic mouse neurons caused a concentration-dependent decrease in A secretion, and this effect was increased by the addition of apolipoprotein A-I. The inhibition of A production by T0901317 was cell-type specific, being more prominent in primary neurons than in non-neuronal cells. Tangier fibroblasts lacking a functional ABCA1 secreted more A than control fibroblasts, thus demonstrating the role of ABCA1 in amyloid precursor protein (APP) processing and A generation. T0901317 treatment of 11-week-old APP23 mice for 6 days showed a significant increase in ABCA1 expression and a decrease in the ratio of soluble APP (sAPP)- to sAPP-cleavage products. Most importantly, the treatment caused a statistically significant reduction in the levels of soluble A₄₀ and of A₄₂ in the brain these mice. Our experiments demonstrate that T0901317 decreases amyloidogenic processing of APP in vitro and in vivo, thus supporting the search for potent and specific LXR ligands with properties allowing therapeutic application.

Received for publication, October 6, 2004 , and in revised form, November 15, 2004.

^* This work was supported by grants from the Pittsburgh Institute for Neurodegenerative Disorders (to R. P. K.), the Alzheimer's Disease Research Center at the University of Pittsburgh (to I. M. L), the National Institutes of Health Grant AG 23304 (to I. M. L.), the Diane and Hal Briedley Chair in Biomedical Research (to M. G. R.), the IMF Foundation (to M. W.), the National Institutes of Health Grant AG 18558 (to J. S. L.), and by the Fiske Drug Discovery Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^¶ To whom correspondence may be addressed: Dept. of Pharmacology, E-1358 Biomedical Science Tower, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. Tel.: 412-648-2052; Fax: 412-648-1945; E-mail: radak{at}pitt.edu. || To whom correspondence may be addressed: Dept. of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. E-mail: iliyal{at}pitt.edu.

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