Expression profiling in APP23 mouse brain

Inhibition of Aß amyloidosis and inflammation in response to LXR agonist treatment

Iliya Lefterov, Angie Bookout, Zhu Wang, Matthias Staufenbiel, David Mangelsdorf, Radosveta Koldamova

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Background: Recent studies demonstrate that in addition to its modulatory effect on APP processing, in vivo application of Liver × Receptor agonist T0901317 (T0) to APP transgenic and non-transgenic mice decreases the level of Aß42. Moreover, in young Tg2576 mice T0 completely reversed contextual memory deficits. Compared to other tissues, the regulatory functions of L×Rs in brain remain largely unexplored and our knowledge so far is limited to the cholesterol transporters and apoE. In this study we applied T0 to APP23 mice for various times and examined gene and protein expression. We also performed a series of experiments with primary brain cells derived from wild type and L×R knockout mice subjected to various L×R agonist treatments and inflammatory stimuli. Results: We demonstrate an upregulation of genes related to lipid metabolism/transport, metabolism of xenobiotics and detoxification. Downregulated genes are involved in immune response and inflammation, cell death and apoptosis. Additional treatment experiments demonstrated an increase of soluble apolipoproteins E and A-I and a decrease of insoluble Aß. In primary L×Rwt but not in L×Rα-/-β-/- microglia and astrocytes L×R agonists suppressed the inflammatory response induced by LPS or fibrillar Aß. Conclusion: The results show that L×R agonists could alleviate AD pathology by acting on amyloid deposition and brain inflammation. An increased understanding of the L×R controlled regulation of Aß aggregation and clearance systems will lead to the development of more specific and powerful agonists targeting L×R for the treatment of AD.

Original languageEnglish (US)
Article number20
JournalMolecular Neurodegeneration
Volume2
Issue number1
DOIs
StatePublished - 2007

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Amyloidosis
Apolipoproteins E
Inflammation
Brain
Apolipoprotein A-I
Memory Disorders
Microglia
Xenobiotics
Encephalitis
Lipid Metabolism
Amyloid
Knockout Mice
Astrocytes
Genes
Cell Death
Up-Regulation
Down-Regulation
Cholesterol
Apoptosis
Pathology

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Expression profiling in APP23 mouse brain : Inhibition of Aß amyloidosis and inflammation in response to LXR agonist treatment. / Lefterov, Iliya; Bookout, Angie; Wang, Zhu; Staufenbiel, Matthias; Mangelsdorf, David; Koldamova, Radosveta.

In: Molecular Neurodegeneration, Vol. 2, No. 1, 20, 2007.

Research output: Contribution to journalArticle

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