[en] Neuroinflammation plays a fundamental role in the pathogenesis of Alzheimer's disease (AD), resulting in the extensive activation of microglial and astroglial cells. Here we describe the role of myeloid-related protein Mrp14, a recently described amplifier of inflammation, in Alzheimer's disease and in the related amyloid precursor protein/presenilin1 (APP/PS1) mouse model. Detection of Mrp14 in control, mildly cognitive impaired, and AD patients revealed a strong induction of Mrp14 in protein extracts as well as in the cerebrospinal fluid, but not in blood plasma. In APP/PS1 mice, Mrp14 and its heterodimeric partner Mrp8 was found to be upregulated in microglial cells surrounding amyloid plaques. Functionally, loss of Mrp14 led to increased phagocytosis of fibrillar amyloid β (Aβ) in microglia cells in vitro and in vivo. Generating APP/PS1-transgenic mice deficient for Mrp14, we observed a decrease of key cytokines involved in APP processing, a reduction of BACE1 expression and activity, and consequently overall Aβ deposition. We therefore conclude that Mrp14 promotes APP processing and Aβ accumulation under neuroinflammatory conditions.
Disciplines :
Neurology
Author, co-author :
Kummer, Markus P; Clinical Neurosciences Unit, Department of Neurology, University of Bonn, 53105 Bonn, Germany
Vogl, Thomas; Institute of Immunology, University of Münster, 48129 Münster, Germany
Axt, Daisy; Clinical Neurosciences Unit, Department of Neurology, University of Bonn, 53105 Bonn, Germany
Griep, Angelika; Clinical Neurosciences Unit, Department of Neurology, University of Bonn, 53105 Bonn, Germany
Vieira-Saecker, Ana; Clinical Neurosciences Unit, Department of Neurology, University of Bonn, 53105 Bonn, Germany
Jessen, Frank; Department of Psychiatry, University of Bonn, 53105 Bonn, Germany ; German Center for Neurodegenerative Diseases, 53175 Bonn, Germany
Gelpi, Ellen; Neurological Tissue Bank, University of Barcelona-Hospital Clinic, August Pi i Sunyer Institute for Biomedical Investigations (IDIBAPS), E-08036 Barcelona, Spain
Roth, Johannes; Institute of Immunology, University of Münster, 48129 Münster, Germany
HENEKA, Michael ; Clinical Neurosciences Unit, Department of Neurology, University of Bonn, 53105 Bonn, Germany ; German Center for Neurodegenerative Diseases, 53175 Bonn, Germany
External co-authors :
yes
Language :
English
Title :
Mrp14 deficiency ameliorates amyloid β burden by increasing microglial phagocytosis and modulation of amyloid precursor protein processing.
Beutler B (2004) Toll-like receptors and their place in immunology. Where does the immune response to infection begin? Nat Rev Immunol 4:498. CrossRef Medline
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. CrossRef Medline
Ehrchen JM, Sunderkötter C, Foell D, Vogl T, Roth J (2009) The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol 86:557-566. CrossRef Medline
Fang F, Lue L-F, Yan S, Xu H, Luddy JS, Chen D, Walker DG, Stern DM, Yan S, Schmidt AM, Chen JX, Yan SS (2010) RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease. FASEB J 24:1043-1055. CrossRef Medline
Gebhardt C, Riehl A, Durchdewald M, Németh J, Fürstenberger G, Müller-Decker K, Enk A, Arnold B, Bierhaus A, Nawroth PP, Hess J, Angel P (2008) RAGE signaling sustains inflammation and promotes tumor development. J Exp Med 205:275-285. CrossRef Medline
Ha T-Y, Chang K-A, Kim J, Kim H-S, Kim S, Chong YH, Suh Y-H (2010) S100a9 knockdown decreases the memory impairment and the neuropathology in Tg2576 mice, AD animal model. PLoS ONE 5:e8840. CrossRef Medline
Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, Van Leuven F (2005) Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation 2:22. CrossRef Medline
Hickman SE, Allison EK, El-Khoury J (2008) Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci 28:8354-8360. CrossRef Medline
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. CrossRef Medline
Klunk WE, Bacskai BJ, Mathis CA, Kajdasz ST, McLellan ME, Frosch MP, Debnath ML, Holt DP, Wang Y, Hyman BT (2002) Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative. J Neuropathol Exp Neurol 61:797-805. Medline
Kummer MP, Hermes M, Delekate A, Hammerschmidt T, Kumar S, Terwel D, Walter J, Pape H-C, König S, Roeber S, Jessen F, Klockgether T, Korte M, Heneka MT (2011) Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron 71:833-844. CrossRef Medline
Manitz M-P, Horst B, Seeliger S, Strey A, Skryabin BV, Gunzer M, Frings W, Schönlau F, Roth J, Sorg C, Nacken W (2003) Loss of S100A9 (MRP14) results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants in vitro. Mol Cell Biol 23:1034-1043. CrossRef Medline
Mariathasan S, Monack DM (2007) Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7:31-40. CrossRef Medline
Mori T, Koyama N, Arendash GW, Horikoshi-Sakuraba Y, Tan J, Town T (2010) Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease. Glia 58:300-314.CrossRef Medline
Mrak RE, Griffin WS (2001) Interleukin-1, neuroinflammation, and Alzheimer's disease. Neurobiol Aging 22:903-908.CrossRef Medline
Oppenheim JJ, Yang D (2005) Alarmins: chemotactic activators of immune responses. Curr Opin Immunol 17:359-365.CrossRef Medline
Roth J, Vogl T, Sorg C, Sunderkötter C (2003) Phagocyte-specific S100 proteins: a novel group of proinflammatory molecules. Trends Immunol 24:155-158. CrossRef Medline
Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, van Leuven F, Heneka MT (2003) Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci 23:9796-9804. Medline
Sastre M, Dewachter I, Rossner S, Bogdanovic N, Rosen E, Borghgraef P, Evert BO, Dumitrescu-Ozimek L, Thal DR, Landreth G, Walter J, Klockgether T, van Leuven F, Heneka MT (2006) Nonsteroidal antiinflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci U S A 103:443-448. CrossRef Medline
Shepherd CE, Goyette J, Utter V, Rahimi F, Yang Z, Geczy CL, Halliday GM (2006) Inflammatory S100A9 and S100A12 proteins in Alzheimer's disease. Neurobiol Aging 27:1554-1563. CrossRef Medline
Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson J-Å, Holtzman DM, Heneka MT (2011) Critical role of astroglial apolipoprotein E and liver X receptor-β expression for microglial Aβ phagocytosis. J Neurosci 31:7049-7059. CrossRef Medline
Town T, Nikolic V, Tan J (2005) The microglial "activation" continuum: from innate to adaptive responses. J Neuroinflammation 2:24. CrossRef Medline
Turovskaya O, Foell D, Sinha P, Vogl T, Newlin R, Nayak J, Nguyen M, Olsson A, Nawroth PP, Bierhaus A, Varki N, Kronenberg M, Freeze HH, Srikrishna G (2008) RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis. Carcinogenesis 29:2035-2043. CrossRef Medline
Vogl T, Ludwig S, Goebeler M, Strey A, Thorey IS, Reichelt R, Foell D, Gerke V, Manitz MP, Nacken W, Werner S, Sorg C, Roth J (2004) MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes. Blood 104:4260-4268. CrossRef Medline
Vogl T, Tenbrock K, Ludwig S, Leukert N, Ehrhardt C, van Zoelen MAD, Nacken W, Foell D, van der Poll T, Sorg C, Roth J (2007) Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med 13:1042-1049. CrossRef Medline
Wahle T, Thal DR, Sastre M, Rentmeister A, Bogdanovic N, Famulok M, Heneka MT, Walter J (2006) GGA1 is expressed in the human brain and affects the generation of amyloid beta-peptide. J Neurosci 26:12838-12846. CrossRef Medline
