[en] We investigated whether peroxisome proliferator-activated receptor gamma (PPARgamma) could be involved in the modulation of the amyloid cascade causing Alzheimer's disease. Inducing expression or activating PPARgamma using synthetic agonists of the thiazolinedione family results in a dramatic decrease in the levels of the amyloid-beta (Abeta) peptide in the conditioned medium of neuronal and non-neuronal cells. PPARgamma does not affect expression or activity of any of the secretases involved in the generation of the Abeta peptide but induces a fast, cell-bound clearing mechanism responsible for the removal of the Abeta peptide from the medium. Although PPARgamma expression is generally low in the CNS, induction of PPARgamma expression during inflammation could be beneficial for inducing Abeta clearance. We confirm that the Abeta clearance mechanism can indeed be induced by PPARgamma activation in primary murine-mixed glia and cortical neuronal cultures. Our results suggest that PPARgamma-controlled mechanisms should be explored further as potential drug targets for Alzheimer's disease treatment.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Espuny Camacho, Ira Mercedes ; VIB, KU Leuven, 3000 Leuven, Belgium > Neuronal Cell Biology and Gene Transfer Laboratory, Center for Human Genetics
Serneels, L; VIB, KU Leuven, 3000 Leuven, Belgium > Neuronal Cell Biology and Gene Transfer Laboratory, Center for Human Genetics
Andrews, N.C., Faller, D.V., A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells (1991) Nucleic Acids Res, 19, p. 2499
Berger, J., Bailey, P., Biswas, C., Cullinan, C.A., Doebber, T.W., Hayes, N.S., Saperstein, R., Leibowitz, M.D., Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: Binding and activation correlate with antidiabetic actions in db/db mice (1996) Endocrinology, 137, pp. 4189-4195
Blumberg, B., Evans, R.M., Orphan nuclear receptors-new ligands and new possibilities (1998) Genes Dev, 12, pp. 3149-3155
Cai, H., Wang, Y., McCarthy, D., Wen, H., Borchelt, D.R., Price, D.L., Wong, P.C., BACE1 is the major beta-secretase for generation of Abeta peptides by neurons (2001) Nat Neurosci, 4, pp. 233-234
Chawla, A., Schwarz, E.J., Dimaculangan, D.D., Lazar, M.A., Peroxisome proliferator-activated receptor (PPAR) gamma: Adipose-predominant expression and induction early in adipocyte differentiation (1994) Endocrinology, 135, pp. 798-800
Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A.Y., Seubert, P., Vigo-Pelfrey, C., Selkoe, D.J., Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production (1992) Nature, 360, pp. 672-674
Colville-Nash, P.R., Qureshi, S.S., Willis, D., Willoughby, D.A., Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists: Correlation with induction of heme oxygenase 1 (1998) J Immunol, 161, pp. 978-984
Combs, C.K., Johnson, D.E., Karlo, J.C., Cannady, S.B., Landreth, G.E., Inflammatory mechanisms in Alzheimer's disease: Inhibition of β-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists (2000) J Neurosci, 20, pp. 558-567
Dehmer, T., Heneka, M.T., Sastre, M., Dichgans, J., Schulz, J.B., Protection by pioglitazone in the MPTP model of Parkinson's disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation (2004) J Neurochem, 88, pp. 494-501
De Strooper, B., Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-secretase complex (2003) Neuron, 38, pp. 9-12
De Strooper, B., Simons, M., Multhaup, G., Van Leuven, F., Beyreuther, K., Dotti, C.G., Production of intracellular amyloid-containing fragments in hippocampal neurons expressing human amyloid precursor protein and protection against amyloidogenesis by subtle amino acid substitutions in the rodent sequence (1995) EMBO J, 14, pp. 4932-4938
De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., Von Figura, K., Van Leuven, F., Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein (1998) Nature, 391, pp. 387-390
De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J.S., Schroeter, E.H., Kopan, R., A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain (1999) Nature, 398, pp. 518-522
Donnelly-Roberts, D.L., Puttfarcken, P.S., Kuntzweiler, T.A., Briggs, C.A., Anderson, D.J., Campbell, J.E., Piattoni-Kaplan, M., Arneric, S.P., ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: A novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. in vitro characterization (1998) J Pharmacol Exp Ther, 285, pp. 777-786
Eriksen, J.L., Sagi, S.A., Smith, T.E., Weggen, S., Das, P., McLendon, D.C., Ozols, V.V., Golde, T.E., NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo (2003) J Clin Invest, 112, pp. 440-449
Francis, R., McGrath, G., Zhang, J., Ruddy, D.A., Sym, M., Apfeld, J., Nicoll, M., Curtis, D., Aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation (2002) Dev Cell, 3, pp. 85-97
Goutte, C., Tsunozaki, M., Hale, V.A., Priess, J.R., APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos (2002) Proc Natl Acad Sci USA, 99, pp. 775-779
Heneka, M.T., Klockgether, T., Feinstein, D.L., Peroxisome proliferator-activated receptor-γ ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo (2000) J Neurosci, 20, pp. 6862-6867
Hu, E., Tontonoz, P., Spiegelman, B.M., Transdifferentiation of myoblasts by the adipogenic transcription factors PPAR gamma and C/EBP alpha (1995) Proc Natl Acad Sci USA, 92, pp. 9856-9860
Huang, J.T., Welch, J.S., Ricote, M., Binder, C.J., Willson, T.M., Kelly, C., Witztum, J.L., Glass, C.K., Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase (1999) Nature, 400, pp. 378-382
Hussain, I., Powell, D., Howlett, D.R., Tew, D.G., Meek, T.D., Chapman, C., Gloger, I.S., Christie, G., Identification of a novel aspartic protease (Asp 2) as beta-secretase (1999) Mol Cell Neurosci, 14, pp. 419-427
Veld, B.A., Ruitenberg, A., Hofman, A., Launer, L.J., Van Duijn, C.M., Stijnen, T., Breteler, M.M., Stricker, B.H., Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease (2001) N Engl J Med, 345, pp. 1515-1521
Jantzen, P.T., Connor, K.E., Dicarlo, G., Wenk, G.L., Wallace, J.L., Rojiani, A.M., Coppola, D., Gordon, M.N., Microglial activation and β-amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice (2002) J Neurosci, 22, pp. 2246-2254
Jarriault, S., Brou, C., Logeat, F., Schroeter, E.H., Kopan, R., Israel, A., Signalling downstream of activated mammalian Notch (1995) Nature, 377, pp. 355-358
Jiang, C., Ting, A.T., Seed, B., PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines (1998) Nature, 391, pp. 82-86
Karlstrom, H., Bergman, A., Lendahl, U., Naslund, J., Lundkvist, J., A sensitive and quantitative assay for measuring cleavage of presenilin substrates (2002) J Biol Chem, 277, pp. 6763-6766
Kitamura, Y., Shimohama, S., Koike, H., Kakimura, J., Matsuoka, Y., Nomura, Y., Gebicke-Haerter, P.J., Taniguchi, T., Increased expression of cyclooxygenases and peroxisome proliferator-activated receptor-gamma in Alzheimer's disease brains (1999) Biochem Biophys Res Commun, 254, pp. 582-586
Klegeris, A., Walker, D.G., McGeer, P.L., Toxicity of human THP-1 monocytic cells towards neuron-like cells is reduced by non-steroidal anti-inflammatory drugs (NSAIDs) (1999) Neuropharmacology, 38, pp. 1017-1025
Koike, H., Tomioka, S., Sorimachi, H., Saido, T.C., Maruyama, K., Okuyama, A., Fujisawa-Sehara, A., Ishiura, S., Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein (1999) Biochem J, 343, pp. 371-375
Kopan, R., Schroeter, E.H., Weintraub, H., Nye, J.S., Signal transduction by activated mNotch: Importance of proteolytic processing and its regulation by the extracellular domain (1996) Proc Natl Acad Sci USA, 93, pp. 1683-1688
Lammich, S., Kojro, E., Postina, R., Gilbert, S., Pfeiffer, R., Jasionowski, M., Haass, C., Fahrenholz, F., Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease (1999) Proc Natl Acad Sci USA, 96, pp. 3922-3927
Lannfelt, L., Viitanen, M., Johansson, K., Axelman, K., Lilius, L., Almqvist, E., Winblad, B., Low frequency of the APP 670/671 mutation in familial Alzheimer's disease in Sweden (1993) Neurosci Lett, 153, pp. 85-87
Lehmann, J.M., Moore, L.B., Smith-Oliver, T.A., Wilkison, W.O., Willson, T.M., Kliewer, S.A., An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) (1995) J Biol Chem, 270, pp. 12953-12956
Lemberger, T., Desvergne, B., Wahli, W., Peroxisome proliferator-activated receptors: A nuclear receptor signaling pathway in lipid physiology (1996) Annu Rev Cell Dev Biol, 12, pp. 335-363
Lim, G.P., Yang, F., Chu, T., Chen, P., Beech, W., Teter, B., Tran, T., Cole, G.M., Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease (2000) J Neurosci, 20, pp. 5709-5714
Mackenzie, I.R., Munoz, D.G., Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging (1998) Neurology, 50, pp. 986-990
Mangelsdorf, D.J., Borgmeyer, U., Heyman, R.A., Zhou, J.Y., Ong, E.S., Oro, A.E., Kakizuka, A., Evans, R.M., Characterization of three RXR genes that mediate the action of 9-cis retinoic acid (1992) Genes Dev, 6, pp. 329-344
Mangelsdorf, D.J., Thummel, C., Beato, M., Herrlich, P., Schutz, G., Umesono, K., Blumberg, B., Chambon, P., The nuclear receptor superfamily: The second decade (1995) Cell, 83, pp. 835-839
McGeer, P.L., McGeer, E.G., Anti-inflammatory drugs in the fight against Alzheimer's disease (1996) Ann NY Acad Sci, 777, pp. 213-220
McGeer, P.L., Kawamata, T., Walker, D.G., Akiyama, H., Tooyama, I., McGeer, E.G., Microglia in degenerative neurological disease (1993) Glia, 7, pp. 84-92
Michiels, F., Van Es, H., Van Rompaey, L., Merchiers, P., Francken, B., Pittois, K., Van Der Schueren, J., Langemeijer, E., Arrayed adenoviral expression libraries for functional screening (2002) Nat Biotechnol, 20, pp. 1154-1157
Miyata, K.S., McCaw, S.E., Marcus, S.L., Rachubinski, R.A., Capone, J.P., The peroxisome proliferator-activated receptor interacts with the retinoid X receptor in vivo (1994) Gene, 148, pp. 327-330
Mukherjee, R., Davies, P.J., Crombie, D.L., Bischoff, E.D., Cesario, R.M., Jow, L., Hamann, L.G., Heyman, R.A., Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists (1997) Nature, 386, pp. 407-410
Nyabi, O., Bentahir, M., Horre, K., Herreman, A., Gottardi-Littell, N., Van Broeckhoven, C., Merchiers, P., De Strooper, B., Presenilins mutated at Asp-257 or Asp-385 restore Pen-2 expression and Nicastrin glycosylation but remain catalytically inactive in the absence of wild type Presenilin (2003) J Biol Chem, 278, pp. 43430-43436
Okano, H., Shiraki, K., Inoue, H., Yamanaka, T., Deguchi, M., Sugimoto, K., Sakai, T., Nakano, T., Peroxisome proliferator-activated receptor gamma augments tumor necrosis factor family-induced apoptosis in hepatocellular carcinoma (2002) Anticancer Drugs, 13, pp. 59-65
Olefsky, J.M., Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists (2000) J Clin Invest, 106, pp. 467-472
Pan, D., Rubin, G.M., Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis (1997) Cell, 90, pp. 271-280
Perlmutter, L.S., Barron, E., Chui, H.C., Morphologic association between microglia and senile plaque amyloid in Alzheimer's disease (1990) Neurosci Lett, 119, pp. 32-36
Petrova, T.V., Akama, K.T., Van Eldik, L.J., Cyclopentenone prostaglandins suppress activation of microglia: Down-regulation of inducible nitric-oxide synthase by 15-deoxy-delta12,14- prostaglandin J2 (1999) Proc Natl Acad Sci USA, 96, pp. 4668-4673
Ricote, M., Huang, J.T., Welch, J.S., Glass, C.K., The peroxisome proliferator-activated receptor(PPARgamma) as a regulator of monocyte/macrophage function (1999) J Leukoc Biol, 66, pp. 733-739
Rosen, E.D., Sarraf, P., Troy, A.E., Bradwin, G., Moore, K., Milstone, D.S., Spiegelman, B.M., Mortensen, R.M., PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro (1999) Mol Cell, 4, pp. 611-617
Rossor, M.N., Newman, S., Frackowiak, R.S., Lantos, P., Kennedy, A.M., Alzheimer's disease families with amyloid precursor protein mutations (1993) Ann NY Acad Sci, 695, pp. 198-202
Sagi, S.A., Weggen, S., Eriksen, J., Golde, T.E., Koo, E.H., The non-cyclooxygenase targets of non-steroidal anti-inflammatory drugs, lipoxygenases, peroxisome proliferator-activated receptor, inhibitor of kappa B kinase, and NF kappa B, do not reduce amyloid beta 42 production (2003) J Biol Chem, 278, pp. 31825-31830
Sastre, M., Dewachter, I., Landreth, G.E., Willson, T.M., Klockgether, T., Van Leuven, F., Heneka, M.T., Nonsteroidal anti-inflammatory drugs and peroxisome proliferator- activated receptor-γ agonists modulate immunostimulated processing of amyloid precursor protein through regulation of β-secretase (2003) J Neurosci, 23, pp. 9796-9804
Sinha, S., Anderson, J.P., Barbour, R., Basi, G.S., Caccavello, R., Davis, D., Doan, M., Schenk, D., Purification and cloning of amyloid precursor protein beta-secretase from human brain (1999) Nature, 402, pp. 537-540. , In Process Citation
Steppan, C.M., Bailey, S.T., Bhat, S., Brown, E.J., Banerjee, R.R., Wright, C.M., Patel, H.R., Lazar, M.A., The hormone resistin links obesity to diabetes (2001) Nature, 409, pp. 307-312
Stewart, W.F., Kawas, C., Corrada, M., Metter, E.J., Risk of Alzheimer's disease and duration of NSAID use (1997) Neurology, 48, pp. 626-632
Tan, J., Town, T., Paris, D., Mori, T., Suo, Z., Crawford, F., Mattson, M.P., Mullan, M., Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation (1999) Science, 286, pp. 2352-2355
Tontonoz, P., Hu, E., Spiegelman, B.M., Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor (1994) Cell, 79, pp. 1147-1156
Vassar, R., Bennett, B.D., Babu-Khan, S., Kahn, S., Mendiaz, E.A., Denis, P., Teplow, D.B., Louis, J.C., Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE (1999) Science, 286, pp. 735-741
Wang, C., Fu, M., D'Amico, M., Albanese, C., Zhou, J.N., Brownlee, M., Lisanti, M.P., Pestell, R.G., Inhibition of cellular proliferation through IkappaB kinase-independent and peroxisome proliferator-activated receptor gamma-dependent repression of cyclin D1 (2001) Mol Cell Biol, 21, pp. 3057-3070
Weggen, S., Eriksen, J.L., Das, P., Sagi, S.A., Wang, R., Pietrzik, C.U., Findlay, K.A., Koo, E.H., A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity (2001) Nature, 414, pp. 212-216
Willson, T.M., Brown, P.J., Sternbach, D.D., Henke, B.R., The PPARs: From orphan receptors to drug discovery (2000) J Med Chem, 43, pp. 527-550
Yan, Q., Zhang, J., Liu, H., Babu-Khan, S., Vassar, R., Biere, A.L., Citron, M., Landreth, G., Anti-inflammatory drug therapy alters β-amyloid processing and deposition in an animal model of Alzheimer's disease (2003) J Neurosci, 23, pp. 7504-7509
Yan, R., Bienkowski, M.J., Shuck, M.E., Miao, H., Tory, M.C., Pauley, A.M., Brashier, J.R., Gurney, M.E., Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity (1999) Nature, 402, pp. 533-537
Yu, G., Nishimura, M., Arawaka, S., Levitan, D., Zhang, L., Tandon, A., Song, Y.Q., Sato, C., Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing (2000) Nature, 407, pp. 48-54
