The Impact of PPAR Signalling on Alzheimer's Disease

Coordinating Institution: Université du Luxembourg
Contracting Partner(s): University of Wageningen (NL)
From: 01/01/2008
To: 31/12/2010
Budget: 241,000.00€
Contact(s): Welter-Stahl Lynn

Summary

Alzheimer’s disease (AD) is an age-dependent neurodegenerative disease that causes progressive cognitive impairment. The initiation and progression of AD has been linked to cholesterol metabolism and inflammation, processes that can be modulated by peroxisome proliferator-activated receptor-g (PPARg) and liver X receptor (LXR). PPARg and LXR are ligand-activated transcription factors that belong to the superfamily of nuclear receptors. The activation of these transcription factors have been associated with potent anti-inflammatory as well as anti-amyloidogenic effects in cell culture and AD animal models.

Unfortunately, very little is known about the molecular mechanisms that subserve these effects. We believe that unraveling the molecular mechanism of these neuroprotective effects is of central importance for the understanding of the pathogenesis of AD. In AD brains, the resident macrophage population, the microglia cells release elevated levels of inflammatory mediators and are defective in the clearance of amyloid-b deposits.

These inappropriate microglia functions are postulated to contribute to neuronal degeneration and cell death in AD patients. Pharmacological modulation of microglia/macrophage gene expression therefore represents an important therapeutic approach for the treatment of AD. We are currently evaluating the effects and consequences of PPAR and LXR activation on monocyte/macrophage differentiation and activation. We performed a global gene expression profiling of PPARg and LXR-treated early differentiating and fully differentiated macrophages using Illumina GeneChips. We observed that PPARg and LXRα is highly induced during differentiation of monocytes to macrophages.

More than 230 genes are regulated in early as well as mature macrophages by activation of LXR; most of them are up-regulated. These changes appear to modulate the genes expression profile associated with macrophage differentiation. In early differentiating macrophages only genes related to lipid and cholesterol metabolism are overrepresented among early induced genes. In contrast, genes related to immune function, cell morphology and .cell proliferation respond at later time points. In contraste, in mature macrophages showing high LXR expression, some of the same functional gene clusters respond far earlier after LXR ligand treatment.

In conclusion, our data suggests that LXR are modulators of macrophage differentiation, acting mostly as positive transcriptional regulators of genes involved in lipid and cholesterol metabolism, as well as genes associated with immune function, morphology and proliferation. The molecular details of the links between lipid metabolism, immune function and proliferation remain to be investigated but clearly some of the novel identified primary LXR and PPAR targets increase our understanding of the control of macrophage/microgia functions by these transcription factors.

Programme:

• FLARE

Foreign Funding Agency:

• Era-Net, ERA-AGE

Refereed Scientific Publications:

• Welter-Stahl L, da Silva CM, Schachter J, Persechini PM, Souza HS, Ojcius DM, Coutinho-Silva R. Expression of purinergic receptors and modulation of P2X(7) function by the inflammatory cytokine IFNgamma in human epithelial cells. Biochim Biophys Acta. 2009 May;1788(5):1176-87.

• Darville T, Welter-Stahl L, Cruz C, Sater AA, Andrews CW Jr, Ojcius DM. Effect of the purinergic receptor P2X7 on Chlamydia infection in cervical epithelial cells and vaginally infected mice. J Immunol. 2007 Sep 15;179(6):3707-14. (Impact factor 2007 6.1)

• Verbeke P, Welter-Stahl L, Ying S, Hansen J, Hacker G, Darville T, Ojcius DM. Recruitment of BAD by the Chlamydia trachomatis vacuole correlates with host-cell survival. PLoS Pathog. 2006 May;2(5):e45. (Impact factor 2006 6.1)

• Welter-Stahl L, Ojcius DM, Viala J, Girardin S, Liu W, Delarbre C, Philpott D, Kelly KA, Darville T. Stimulation of the cytosolic receptor for peptidoglycan, Nod1, by infection with Chlamydia trachomatis or Chlamydia muridarum. Cell Microbiol. 2006 Jun;8(6):1047-57. (Impact factor 2006 5.1)

• Nagarajan UM, Ojcius DM, Stahl L, Rank RG, Darville T. Chlamydia trachomatis induces expression of IFN-gamma-inducible protein 10 and IFN-beta independent of TLR2 and TLR4, but largely dependent on MyD88. J Immunol. 2005 Jul 1;175(1):450-60. (Impact factor 2005 6.4)

• Coutinho-Silva R, Stahl L, Cheung KK, de Campos NE, de Oliveira Souza C, Ojcius DM, Burnstock G. P2X and P2Y purinergic receptors on human intestinal epithelial carcinoma cells: effects of extracellular nucleotides on apoptosis and cell proliferation. Am J Physiol Gastrointest Liver Physiol. 2005 May;288(5):G1024-35. (Impact factor 2005 3.5)

• Darville T, O'Neill JM, Andrews CW Jr, Nagarajan UM, Stahl L, Ojcius DM. Toll-like receptor-2, but not Toll-like receptor-4, is essential for development of oviduct pathology in chlamydial genital tract infection. J Immunol. 2003 Dec 1;171(11):6187-97. (Impact factor 2003 6.7)

• Perfettini JL, Hospital V, Stahl L, Jungas T, Verbeke P, Ojcius DM. Cell death and inflammation during infection with the obligate intracellular pathogen, Chlamydia. Biochimie. 2003 Aug;85(8):763-9. Review. (Impact factor 2003 3.7)

• Coutinho-Silva R, Stahl L, Raymond MN, Jungas T, Verbeke P, Burnstock G, Darville T, Ojcius DM. Inhibition of chlamydial infectious activity due to P2X7R-dependent phospholipase D activation. Immunity. 2003 Sep;19(3):403-12. (Impact factor 2003 16.0)

Other Publications:

• Verbeke P, Welter-Stahl L, Jungas T, Delarbre C, and Ojcius DM. A pathogen with two personalities: death and survival during infection with Chlamydia. In Chlamydia: Genomics, Pathogenesis and Implications for Control, 1st edition, Bavoil P and Wyrick P (eds), Harcourt Press.