Top

Published in:

Open Access 01-12-2018 | Research

Glycoprotein NMB: a novel Alzheimer’s disease associated marker expressed in a subset of activated microglia

Authors: Melanie Hüttenrauch, Isabella Ogorek, Hans Klafki, Markus Otto, Christine Stadelmann, Sascha Weggen, Jens Wiltfang, Oliver Wirths

Published in: Acta Neuropathologica Communications | Issue 1/2018

Abstract

Alzheimer’s disease (AD) is an irreversible, devastating neurodegenerative brain disorder characterized by the loss of neurons and subsequent cognitive decline. Despite considerable progress in the understanding of the pathophysiology of AD, the precise molecular mechanisms that cause the disease remain elusive. By now, there is ample evidence that activated microglia have a critical role in the initiation and progression of AD. The present study describes the identification of Glycoprotein nonmetastatic melanoma protein B (GPNMB) as a novel AD-related factor in both transgenic mice and sporadic AD patients by expression profiling, immunohistochemistry and ELISA measurements. We show that GPNMB levels increase in an age-dependent manner in transgenic AD models showing profound cerebral neuron loss and demonstrate that GPNMB co-localizes with a distinct population of IBA1-positive microglia cells that cluster around amyloid plaques. Our data further indicate that GPNMB is part of a microglia activation state that is only present under neurodegenerative conditions and that is characterized by the up-regulation of a subset of genes including TREM2, APOE and CST7. In agreement, we provide in vitro evidence that soluble Aβ has a direct effect on GPNMB expression in an immortalized microglia cell line. Importantly, we show for the first time that GPNMB is elevated in brain samples and cerebrospinal fluid (CSF) of sporadic AD patients when compared to non-demented controls.

The current findings indicate that GPNMB represents a novel disease-associated marker that appears to play a role in the neuroinflammatory response of AD.

Available only for authorised users

Abdelmagid SM, Barbe MF, Rico MC, Salihoglu S, Arango-Hisijara I, Selim AH, Anderson MG, Owen TA, Popoff SN, Safadi FF (2008) Osteoactivin, an anabolic factor that regulates osteoblast differentiation and function. Exp Cell Res 314:2334–2351CrossRef

Bondolfi L, Calhoun M, Ermini F, Kuhn HG, Wiederhold KH, Walker L, Staufenbiel M, Jucker M (2002) Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice. J Neurosci 22:515–522CrossRef

Breyhan H, Wirths O, Duan K, Marcello A, Rettig J, Bayer TA (2009) APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy. Acta Neuropathol 117:677–685CrossRef

Budge KM, Neal ML, Richardson JR, Safadi FF (2018) Glycoprotein NMB: an emerging role in neurodegenerative disease. Mol Neurobiol 55:5167–5176CrossRef

Casas C, Sergeant N, Itier JM, Blanchard V, Wirths O, van der Kolk N, Vingtdeux V, van de Steeg E, Ret G, Canton T et al (2004) Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 165:1289–1300CrossRefPubMed

Christensen DZ, Kraus SL, Flohr A, Cotel MC, Wirths O, Bayer TA (2008) Transient intraneuronal Abeta rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice. Acta Neuropathol 116:647–655CrossRef

Eimer WA, Vassar R (2013) Neuron loss in the 5XFAD mouse model of Alzheimer's disease correlates with intraneuronal Abeta42 accumulation and Caspase-3 activation. Mol Neurodegener 8:2CrossRefPubMed

Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JSK, Younkin S et al (2013) TREM2 variants in Alzheimer's disease. N Engl J Med 368:117–127CrossRef

Gutknecht M, Geiger J, Joas S, Dörfel D, Salih HR, Müller MR, Grünebach F, Rittig SM (2015) The transcription factor MITF is a critical regulator of GPNMB expression in dendritic cells. Cell Communication and Signaling 13:19CrossRef

10.

Hansen DV, Hanson JE, Sheng M (2018) Microglia in Alzheimer’s disease. J Cell Biol 217:459–472CrossRefPubMed

11.

Henjum K, Almdahl IS, Årskog V, Minthon L, Hansson O, Fladby T, Nilsson LNG (2016) Cerebrospinal fluid soluble TREM2 in aging and Alzheimer’s disease. Alzheimers Res Ther 8:17CrossRefPubMed

12.

Heslegrave A, Heywood W, Paterson R, Magdalinou N, Svensson J, Johansson P, Öhrfelt A, Blennow K, Hardy J, Schott J et al (2016) Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer’s disease. Mol Neurodegener 11:3CrossRefPubMed

13.

Hollingworth P, Harold D, Sims R, Gerrish A, Lambert J-C, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, et al: Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 2011, 43:429

14.

Hopperton KE, Mohammad D, Trépanier MO, Giuliano V, Bazinet RP (2018) Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review. Mol Psychiatry 23:177–198CrossRef

15.

Huang J-J, Ma W-J, Yokoyama S (2012) Expression and immunolocalization of Gpnmb, a glioma-associated glycoprotein, in normal and inflamed central nervous systems of adult rats. Brain and Behavior 2:85–96CrossRefPubMed

16.

Hüttenrauch M, Baches S, Gerth J, Bayer TA, Weggen S, Wirths O (2015) Neprilysin deficiency alters the neuropathological and behavioral phenotype in the 5XFAD mouse model of Alzheimer's disease. J Alzheimers Dis 44:1291–1302CrossRef

17.

International Parkinson’s Disease Genomics C, Wellcome Trust Case Control C (2011) A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease. PLoS Genet 7:e1002142CrossRef

18.

Ishii J, Kitazawa R, Mori K, McHugh KP, Morii E, Kondo T, Kitazawa S (2008) Lipopolysaccharide suppresses RANK gene expression in macrophages by down-regulating PU.1 and MITF. J Cell Biochem 105:896–904CrossRef

19.

Jawhar S, Trawicka A, Jenneckens C, Bayer TA, Wirths O (2012) Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Abeta aggregation in the 5XFAD mouse model of Alzheimer's disease. Neurobiol Aging 33(196):e129–e196 e140

20.

Kamphuis W, Kooijman L, Schetters S, Orre M, Hol EM (2016) Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer's disease. Biochim Biophys Acta (BBA) - Mol Basis Dis 1862:1847–1860CrossRef

21.

Karch CM, Goate AM (2015) Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77:43–51CrossRef

22.

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B et al (2017) A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell 169:1276–1290 e1217CrossRefPubMed

23.

Kramer G, Wegdam W, Donker-Koopman W, Ottenhoff R, Gaspar P, Verhoek M, Nelson J, Gabriel T, Kallemeijn W, Boot RG et al (2016) Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease patients and mouse models. FEBS Open Bio 6:902–913CrossRefPubMed

24.

Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O’Loughlin E, Xu Y, Fanek Z et al (2017) The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity 47:566–581 e569CrossRefPubMed

25.

Kuan C-T, Wakiya K, Dowell JM, Herndon JE, Reardon DA, Graner MW, Riggins GJ, Wikstrand CJ, Bigner DD (2006) Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma Multiforme. Clin Cancer Res 12:1970–1982CrossRef

26.

Lambert J-C, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, et al: Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 2009, 41:1094CrossRef

27.

Landel V, Baranger K, Virard I, Loriod B, Khrestchatisky M, Rivera S, Benech P, Feron F (2014) Temporal gene profiling of the 5XFAD transgenic mouse model highlights the importance of microglial activation in Alzheimer's disease. Mol Neurodegener 9:33CrossRefPubMed

28.

Marques ARA, Gabriel TL, Aten J, van Roomen CPAA, Ottenhoff R, Claessen N, Alfonso P, Irún P, Giraldo P, Aerts JMFG, van Eijk M (2016) Gpnmb is a potential marker for the visceral pathology in Niemann-pick type C disease. PLoS One 11:e0147208CrossRefPubMed

29.

Munter LM, Voigt P, Harmeier A, Kaden D, Gottschalk KE, Weise C, Pipkorn R, Schaefer M, Langosch D, Multhaup G (2007) GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42. EMBO J 26:1702–1712CrossRefPubMed

30.

Nagahara Y, Shimazawa M, Ohuchi K, Ito J, Takahashi H, Tsuruma K, Kakita A, Hara H (2017) GPNMB ameliorates mutant TDP-43-induced motor neuron cell death. J Neurosci Res 95:1647–1665CrossRef

31.

Naj AC, Jun G, Beecham GW, Wang L-S, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK, et al: Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet 2011, 43:436

32.

Neal ML, Boyle AM, Budge KM, Safadi FF, Richardson JR (2018) The glycoprotein GPNMB attenuates astrocyte inflammatory responses through the CD44 receptor. J Neuroinflammation 15:73CrossRefPubMed

33.

Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L et al (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129–10140CrossRef

34.

Ogawa T, Nikawa T, Furochi H, Kosyoji M, Hirasaka K, Suzue N, Sairyo K, Nakano S, Yamaoka T, Itakura M et al (2005) Osteoactivin upregulates expression of MMP-3 and MMP-9 in fibroblasts infiltrated into denervated skeletal muscle in mice. Am J Phys Cell Phys 289:C697–C707CrossRef

35.

Orre M, Kamphuis W, Osborn LM, Jansen AHP, Kooijman L, Bossers K, Hol EM (2014) Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction. Neurobiol Aging 35:2746–2760CrossRef

36.

Piccio L, Deming Y, Del-Águila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C (2016) Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol 131:925–933CrossRefPubMed

37.

Plotegher N, Duchen MR (2017) Mitochondrial dysfunction and neurodegeneration in lysosomal storage disorders. Trends Mol Med 23:116–134CrossRef

38.

Reinert J, Richard BC, Klafki HW, Friedrich B, Bayer TA, Wiltfang J, Kovacs GG, Ingelsson M, Lannfelt L, Paetau A et al (2016) Deposition of C-terminally truncated Aβ species Aβ37 and Aβ39 in Alzheimer’s disease and transgenic mouse models. Acta Neuropathologica Communications 4:1–12CrossRef

39.

Ripoll VM, Irvine KM, Ravasi T, Sweet MJ, Hume DA (2007) Gpnmb is induced in macrophages by IFN-γ and lipopolysaccharide and acts as a feedback regulator of Proinflammatory responses. J Immunol 178:6557–6566CrossRef

40.

Rose AAN, Annis MG, Dong Z, Pepin F, Hallett M, Park M, Siegel PM (2010) ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with Angiogenic properties. PLoS One 5:e12093CrossRefPubMed

41.

Saul A, Sprenger F, Bayer TA, Wirths O (2013) Accelerated tau pathology with synaptic and neuronal loss in a novel triple transgenic mouse model of Alzheimer's disease. Neurobiol Aging 34:2564–2573CrossRef

42.

Schieb H, Kratzin H, Jahn O, Mobius W, Rabe S, Staufenbiel M, Wiltfang J, Klafki HW (2011) Beta-amyloid peptide variants in brains and cerebrospinal fluid from amyloid precursor protein (APP) transgenic mice: comparison with human Alzheimer amyloid. J Biol Chem 286:33747–33758CrossRefPubMed

43.

Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108CrossRefPubMed

44.

Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Molecular Medicine 8:595–608CrossRefPubMed

45.

Stalder M, Phinney A, Probst A, Sommer B, Staufenbiel M, Jucker M (1999) Association of microglia with amyloid plaques in brains of APP23 transgenic mice. Am J Pathol 154:1673–1684CrossRefPubMed

46.

Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P, Paganetti PA et al (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 94:13287–13292CrossRefPubMed

47.

Suárez-Calvet M, Kleinberger G, Araque Caballero MÁ, Brendel M, Rominger A, Alcolea D, Fortea J, Lleó A, Blesa R, Gispert JD et al (2016) sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer's disease and associate with neuronal injury markers. EMBO Molecular Medicine 8:466–476CrossRefPubMed

48.

Tanaka H, Shimazawa M, Kimura M, Takata M, Tsuruma K, Yamada M, Takahashi H, Hozumi I (2012) Niwa J-i, Iguchi Y, et al: The potential of GPNMB as novel neuroprotective factor in amyotrophic lateral sclerosis. Sci Rep 2:573

49.

Tseveleki V, Rubio R, Vamvakas S-S, White J, Taoufik E, Petit E, Quackenbush J, Probert L (2010) Comparative gene expression analysis in mouse models for multiple sclerosis, Alzheimer's disease and stroke for identifying commonly regulated and disease-specific gene changes. Genomics 96:82–91CrossRefPubMed

50.

Walker DG, Lue L-F (2015) Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res Ther 7:56CrossRefPubMed

51.

Weissmann R, Huttenrauch M, Kacprowski T, Bouter Y, Pradier L, Bayer TA, Kuss AW, Wirths O (2016) Gene expression profiling in the APP/PS1KI mouse model of familial Alzheimer's disease. J Alzheimers Dis 50:397–409CrossRef

52.

Weterman MAJ, Ajubi N, van Dinter IMR, Degen WGJ, van Muijen GNP, Ruiter DJ (1995) Bloemers HPJ: nmb, a novel gene, is expressed in low-metastatic human melanoma cell lines and xenografts. Int J Cancer 60:73–81CrossRef

53.

Williams MD, Esmaeli B, Soheili A, Simantov R, Gombos DS, Bedikian AY, Hwu P (2010) GPNMB expression in uveal melanoma: a potential for targeted therapy. Melanoma Res 20:184–190

54.

Wirths O, Bayer TA (2012) Intraneuronal Abeta accumulation and neurodegeneration: lessons from transgenic models. Life Sci 91:1148–1152CrossRef

55.

Wirths O, Breyhan H, Schafer S, Roth C, Bayer TA (2008) Deficits in working memory and motor performance in the APP/PS1ki mouse model for Alzheimer's disease. Neurobiol Aging 29:891–901CrossRef

56.

Wu H-C, Chen C-M, Chen Y-C, Fung H-C, Chang K-H, Wu Y-R (2018) DLG2, but not TMEM229B, GPNMB, and ITGA8 polymorphism, is associated with Parkinson's disease in a Taiwanese population. Neurobiology of Aging 64(158):e151–e158 e156

57.

Xu Y, Chen Y, Ou R, Wei Q-Q, Cao B, Chen K, Shang H-F (2016) No association of GPNMB rs156429 polymorphism with Parkinson’s disease, amyotrophic lateral sclerosis and multiple system atrophy in Chinese population. Neurosci Lett 622:113–117CrossRef

58.

Yin Z, Raj D, Saiepour N, Van Dam D, Brouwer N, Holtman IR, Eggen BJL, Möller T, Tamm JA, Abdourahman A et al (2017) Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer's disease. Neurobiol Aging 55:115–122CrossRef

59.

Yu B, Alboslemy T, Safadi F, Kim M-H (2018) Glycoprotein nonmelanoma clone B regulates the crosstalk between macrophages and mesenchymal stem cells toward wound repair. J Investig Dermatol 138:219–227CrossRef

60.

Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947CrossRefPubMed

61.

Zhou L, Zhuo H, Ouyang H, Liu Y, Yuan F, Sun L, Liu F, Liu H (2017) Glycoprotein non-metastatic melanoma protein b (Gpnmb) is highly expressed in macrophages of acute injured kidney and promotes M2 macrophages polarization. Cell Immunol 316:53–60CrossRef

62.

Zigdon H, Savidor A, Levin Y, Meshcheriakova A, Schiffmann R, Futerman AH (2015) Identification of a biomarker in cerebrospinal fluid for Neuronopathic forms of Gaucher disease. PLoS One 10:e0120194CrossRefPubMed

Title: Glycoprotein NMB: a novel Alzheimer’s disease associated marker expressed in a subset of activated microglia
Authors: Melanie Hüttenrauch
Isabella Ogorek
Hans Klafki
Markus Otto
Christine Stadelmann
Sascha Weggen
Jens Wiltfang
Oliver Wirths
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2018
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-018-0612-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Glycoprotein NMB: a novel Alzheimer’s disease associated marker expressed in a subset of activated microglia

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2018

Prion infectivity is encoded exclusively within the structure of proteinase K-resistant fragments of synthetically generated recombinant PrPSc

Pharmacological inhibition of HDAC6 reverses cognitive impairment and tau pathology as a result of cisplatin treatment

TERT promoter wild-type glioblastomas show distinct clinical features and frequent PI3K pathway mutations

Large inter- and intra-case variability of first generation tau PET ligand binding in neurodegenerative dementias

Long term follow-up and further molecular and histopathological studies in the LGMD1F sporadic TNPO3-mutated patient

A common antigenic motif recognized by naturally occurring human VH5–51/VL4–1 anti-tau antibodies with distinct functionalities