[en] Alzheimer's disease (AD) is characterized by the extracellular deposition of amyloid-β (Aβ), neurofibrillary tangle formation, and a microglial-driven inflammatory response. Chronic inflammatory activation compromises microglial clearance functions. Because peroxisome proliferator-activated receptor γ (PPARγ) agonists suppress inflammatory gene expression, we tested whether activation of PPARγ would also result in improved microglial Aβ phagocytosis. The PPARγ agonist pioglitazone and a novel selective PPARα/γ modulator, DSP-8658, currently in clinical development for the treatment of type 2 diabetes, enhanced the microglial uptake of Aβ in a PPARγ-dependent manner. This PPARγ-stimulated increase of Aβ phagocytosis was mediated by the upregulation of scavenger receptor CD36 expression. In addition, combined treatment with agonists for the heterodimeric binding partners of PPARγ, the retinoid X receptors (RXRs), showed additive enhancement of the Aβ uptake that was mediated by RXRα activation. Evaluation of DSP-8658 in the amyloid precursor protein/presenilin 1 mouse model confirmed an increased microglial Aβ phagocytosis in vivo, which subsequently resulted in a reduction of cortical and hippocampal Aβ levels. Furthermore, DSP-8658-treated mice showed improved spatial memory performance. Therefore, stimulation of microglial clearance by simultaneous activation of the PPARγ/RXRα heterodimer may prove beneficial in prevention of AD.
Disciplines :
Neurology
Author, co-author :
Yamanaka, Mitsugu; Clinical Neuroscience Unit, Department of Neurology, University of Bonn Medical Center, 53127 Bonn, Germany
Ishikawa, Taizo; Clinical Neuroscience Unit, Department of Neurology, University of Bonn Medical Center, 53127 Bonn, Germany ; Dainippon Sumitomo Pharma, 564-0053 Osaka, Japan
Griep, Angelika; Clinical Neuroscience Unit, Department of Neurology, University of Bonn Medical Center, 53127 Bonn, Germany
Axt, Daisy; Clinical Neuroscience Unit, Department of Neurology, University of Bonn Medical Center, 53127 Bonn, Germany
Kummer, Markus P; Clinical Neuroscience Unit, Department of Neurology, University of Bonn Medical Center, 53127 Bonn, Germany
HENEKA, Michael ; Clinical Neuroscience Unit, Department of Neurology, University of Bonn Medical Center, 53127 Bonn, Germany ; German Center for Neurodegenerative Diseases, 53127 Bonn, Germany
External co-authors :
yes
Language :
English
Title :
PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice.
Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE (2003) A cell surface receptor complex for fibrillar /3-amyloid mediates microglial activation. J Neurosci 23:2665-2674.
Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, Kohsaka S, Jucker M, Calhoun ME (2008) Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci 28:4283-4292.
Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP (2006) Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 3:27.
Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE (2000) Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists. J Neurosci 20:558-567.
Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, Luster AD, Silverstein SC, El-Khoury JB (2002) CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol 160:101-112.
Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE (2012) ApoE-directed therapeutics rapidly clear /3-amyloid and reverse deficits in AD mouse models. Science 335:1503-1506.
El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, Freeman MW, Luster AD (2003) CD36 mediates the innate host response to beta-amyloid. J Exp Med 197:1657-1666.
El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13:432-438.
Fleisher-Berkovich S, Filipovich-Rimon T, Ben-Shmuel S, Hülsmann C, Kummer MP, Heneka MT (2010) Distinct modulation of microglial amyloid /3 phagocytosis and migration by neuropeptides (i). J Neuroinflammation 7:61.
Floden AM, Combs CK (2006) /3-Amyloid stimulates murine postnatal and adult microglia cultures in a unique manner. J Neurosci 26:4644-4648.
Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387-1394.
Heneka MT, Landreth GE (2007) PPARs in the brain. Biochim Biophys Acta 1771:1031-1045.
Heneka MT, Feinstein DL, Galea E, Gleichmann M, Wüllner U, Klockgether T (1999) Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase. J Neuroimmunol 100:156-168.
Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, O'Banion K, Klockgether T, Van Leuven F, Landreth GE (2005) Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 128:1442-1453.
Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, Kummer MP (2010a) Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci USA 107:6058-6063.
Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective /3-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci 28:8354-8360.
in t'Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, Breteler MM, Stricker BH (2001) Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med 345:1515-1521.
Jäger S, Leuchtenberger S, Martin A, Czirr E, Wesselowski J, Dieckmann M, Waldron E, Korth C, Koo EH, Heneka M, Weggen S, Pietrzik CU (2009) Alpha-secretase mediated conversion of the Amyloid Precursor Protein derived membrane stub C99 to C83 limits Abeta generation. J Neurochem 111:1369-1382.
Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR (2001) Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 17:157-165.
Jiang C, Ting AT, Seed B (1998) PPARgamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391:82-86.
Lee CY, Landreth GE (2010) The role of microglia in amyloid clearance from the AD brain. J Neural Transm 117:949-960.
Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA (1997) Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 272:3406-3410.
Lucin KM, Wyss-Coray T (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64:110-122.
Maeshiba Y, Kiyota Y, Yamashita K, Yoshimura Y, Motohashi M, Tanayama S (1997) Disposition of the new antidiabetic agent pioglitazone in rats, dogs, and monkeys. Arzneimittelforschung 47:29-35.
McGeer PL, Schulzer M, McGeer EG (1996) Arthritis and antiinflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 47:425-432.
Papi A, Tatenhorst L, Terwel D, Hermes M, Kummer MP, Orlandi M, Heneka MT (2009) PPARgamma and RXRgamma ligands act synergistically as potent antineoplastic agents in vitro and in vivo glioma models. J Neurochem 109:1779-1790.
Ransohoff RM (2009) Chemokines and chemokine receptors: standing at the crossroads of immunobiology and neurobiology. Immunity 31:711-721.
Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK (1998) The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391:79-82.
Rogers J, Lue LF (2001) Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer's disease. Neurochem Int 39:333-340.
Stewart WF, Kawas C, Corrada M, Metter EJ (1997) Risk of Alzheimer's disease and duration of NSAID use. Neurology 48:626-632.
Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson JÅ, Holtz-man DM, Heneka MT (2011) Critical role of astroglial apolipoprotein E and liver X receptor-a expression for microglial Aβ phagocytosis. J Neu-rosci 31:7049-7059.
Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM (1998) PPAR-gamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241-252.
Town T, Nikolic V, Tan J (2005) The microglial "activation" continuum: from innate to adaptive responses. J Neuroinflammation 2:24.
Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA (2008) Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 14:681-687.
Tugwood JD, Issemann I, Anderson RG, Bundell KR, McPheat WL, Green S (1992) The mouse peroxisome proliferator activated receptor recognizes a response element in the 5' flanking sequence of the rat acyl CoA oxidase gene. EMBO J 11:433-439.
Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G (2003) Anti-inflammatory drug therapy alters jS-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci 23:7504-7509.
Zhao X, Grotta J, Gonzales N, Aronowski J (2009) Hematoma resolution as a therapeutic target: the role of microglia/macrophages. Stroke 40:S92-S94.
