The liver X receptor ligaun T0901317 decreases amyloid β 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, John S. Lazo

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Abstract

Recent studies indicate that oxysterols, which are ligands for the nuclear hormone liver X receptors (LXK), decrease amyloid β (Aβ) secretion in vitro. The effect was attributed primarily to the ATP-foinding 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 Aβ 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 Aβ secretion, and this effect was increased by the addition of apolipoprotein A-I. The inhibition of Aβ production type specific, being more prominent in primary neurons than in non-neuronal cells. Tangier fibroblasts lacking a functional ABCA1 secreted more Aβ than control fibroblasts, thus demonstrating the role of ABCA1 in amyloid precursor protein (APP) processing and Aβ 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)β- to sAPPα-cleavage products. Most importantly, the treatment caused a statistically significant reduction in the levels of soluble Aα40 and Aα42 in the brain of 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.

Original languageEnglish (US)
Pages (from-to)4079-4088
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number6
DOIs
StatePublished - Feb 11 2005

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Koldamova, R. P., Lefterov, I. M., Staufenbiel, M., Wolfe, D., Huang, S., Glorioso, J. C., Walter, M., Roth, M. G., & Lazo, J. S. (2005). The liver X receptor ligaun T0901317 decreases amyloid β production in vitro and in a mouse model of Alzheimer's disease. Journal of Biological Chemistry, 280(6), 4079-4088. https://doi.org/10.1074/jbc.M411420200