Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2015

Open Access 01-12-2015 | Research

Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis

Authors: Inge R Holtman, Divya D Raj, Jeremy A Miller, Wandert Schaafsma, Zhuoran Yin, Nieske Brouwer, Paul D Wes, Thomas Möller, Marie Orre, Willem Kamphuis, Elly M Hol, Erik W G M Boddeke, Bart J L Eggen

Published in: Acta Neuropathologica Communications | Issue 1/2015

Login to get access

Abstract

Introduction

Microglia are tissue macrophages of the central nervous system that monitor brain homeostasis and react upon neuronal damage and stress. Aging and neurodegeneration induce a hypersensitive, pro-inflammatory phenotype, referred to as primed microglia. To determine the gene expression signature of priming, the transcriptomes of microglia in aging, Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS) mouse models were compared using Weighted Gene Co-expression Network Analysis (WGCNA).

Results

A highly consistent consensus transcriptional profile of up-regulated genes was identified, which prominently differed from the acute inflammatory gene network induced by lipopolysaccharide (LPS). Where the acute inflammatory network was significantly enriched for NF-κB signaling, the primed microglia profile contained key features related to phagosome, lysosome, antigen presentation, and AD signaling. In addition, specific signatures for aging, AD, and ALS were identified.

Conclusion

Microglia priming induces a highly conserved transcriptional signature with aging- and disease-specific aspects.
Appendix
Available only for authorised users
Literature
1.
Zhang B, Gaiteri C, Bodea L-G, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, Fluder E, Clurman B, Melquist S, Narayanan M, Suver C, Shah H, Mahajan M, Gillis T, Mysore J, MacDonald ME, John R, Lamb JR, Bennett DA, Molony C, David J, Stone DJ, Gudnason V, Myers AJ, Schadt EE, Neumann H (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153:707–20CrossRefPubMedCentralPubMed
2.
Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ, Cotman CW (2012) Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J Neuroinflammation 9:179CrossRefPubMedCentralPubMed
3.
Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, Zuccato C, Cattaneo E, Gage FH, Cleveland DW, Glass CK (2014) Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci 17:513–521CrossRefPubMedCentralPubMed
4.
Chiu IM, Morimoto ETA, Goodarzi H, Liao JT, O’Keeffe S, Phatnani HP, Muratet M, Carroll MC, Levy S, Tavazoie S, Myers RM, Maniatis T (2013) A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep 4:385–401CrossRefPubMedCentralPubMed
5.
Li MD, Burns TC, Morgan AA, Khatri P (2014) Integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases. Acta Neuropathol Commun 2:93CrossRefPubMedCentralPubMed
6.
Kettenmann H, Hanisch U-K, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553CrossRefPubMed
7.
8.
Boche D, Perry VH, Nicoll JAR (2013) Review: Activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39:3–18CrossRefPubMed
9.
Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nat Rev Neurol 10:217–24CrossRefPubMed
10.
Raj DDA, Jaarsma D, Holtman IR, Olah M, Ferreira FM, Schaafsma W, Brouwer N, Meijer MM, de Waard MC, van der Pluijm I, Brandt R, Kreft KL, Laman JD, de Haan G, Biber KPH, Hoeijmakers JHJ, Eggen BJL, Boddeke HWGM (2014) Priming of microglia in a DNA-repair deficient model of accelerated aging. Neurobiol Aging 35:2147–60CrossRefPubMed
11.
Norden DM, Godbout JP (2012) Microglia of the Aged Brain: Primed to be Activated and Resistant to Regulation. Neuropathol Appl Neurobiol. doi: 10.1111/j.1365-2990.2012.01306.x
12.
13.
Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Ashe KH (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481CrossRefPubMedCentralPubMed
14.
Dalby NO, Volbracht C, Helboe L, Larsen PH, Jensen HS, Egebjerg J, Elvang AB (2014) Altered function of hippocampal CA1 pyramidal neurons in the rTg4510 mouse model of tauopathy. J Alzheimers Dis 40:429–42PubMed
15.
Lunnon K, Teeling JL, Tutt AL, Cragg MS, Glennie MJ, Perry VH (2011) Systemic inflammation modulates Fc receptor expression on microglia during chronic neurodegeneration. J Immunol 186:7215–24CrossRefPubMed
16.
Xiang W, Windl O, Wünsch G, Dugas M, Kohlmann A, Dierkes N, Westner IM, Kretzschmar HA (2004) Identification of differentially expressed genes in scrapie-infected mouse brains by using global gene expression technology. J Virol 78:11051–60CrossRefPubMedCentralPubMed
17.
18.
19.
Miller JA, Horvath S, Geschwind DH (2010) Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. Proc Natl Acad Sci U S A 107:12698–703CrossRefPubMedCentralPubMed
20.
21.
Miller JA, Woltjer RL, Goodenbour JM, Horvath S, Geschwind DH (2013) Genes and pathways underlying regional and cell type changes in Alzheimer’s disease. Genome Med 5:48CrossRefPubMedCentralPubMed
22.
23.
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. doi: 10.1016/j.neurobiolaging.2014.06.004
24.
Wirz KTS, Bossers K, Stargardt A, Kamphuis W, Swaab DF, Hol EM, Verhaagen J (2013) Cortical beta amyloid protein triggers an immune response, but no synaptic changes in the APPswe/PS1dE9 Alzheimer’s disease mouse model. Neurobiol Aging 34:1328–42CrossRefPubMed
25.
Kedmi M, Orr-Urtreger A (2011) The effects of aging vs. α7 nAChR subunit deficiency on the mouse brain transcriptome: aging beats the deficiency. Age (Dordr) 33:1–13CrossRef
26.
Xiang W, Hummel M, Mitteregger G, Pace C, Windl O, Mansmann U, Kretzschmar HA (2007) Transcriptome analysis reveals altered cholesterol metabolism during the neurodegeneration in mouse scrapie model. J Neurochem 102:834–47CrossRefPubMed
27.
El Chartouni C, Rehli M Comprehensive analysis of TLR4-induced transcriptional responses in interleukin 4-primed mouse macrophages. Immunobiology 215:780–7.
28.
Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28:8354–60CrossRefPubMedCentralPubMed
29.
Smyth GK (2005) Limma : Linear Models for Microarray Data. Bioinformatics pages:397–420.
30.
Johnson WE, Li C, Rabinovic A (2007) Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8:118–27CrossRefPubMed
31.
Gautier L, Cope L, Bolstad BM, Irizarry RA (2004) affy–analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20:307–15CrossRefPubMed
32.
Zhang B, Kirov S, Snoddy J (2005) WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res 33:W741–8CrossRefPubMedCentralPubMed
33.
Miller JA, Cai C, Langfelder P, Geschwind DH, Kurian SM, Salomon DR, Horvath S (2011) Strategies for aggregating gene expression data: the collapseRows R function. BMC Bioinformatics 12:322CrossRefPubMedCentralPubMed
34.
Martinez FO, Helming L, Milde R, Varin A, Melgert BN, Draijer C, Thomas B, Fabbri M, Crawshaw A, Ho LP, Ten Hacken NH, Cobos Jimenez V, Kootstra NA, Hamann J, Greaves DR, Locati M, Mantovani A, Gordon S (2013) Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences. Blood 121:e57–69CrossRefPubMed
35.
Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26:139–40CrossRefPubMedCentralPubMed
36.
Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang L, Means TK, El Khoury J (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16:1896–905CrossRefPubMed
37.
Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL (2014) Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–43CrossRefPubMedCentralPubMed
38.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–50CrossRefPubMedCentralPubMed
39.
Venkatesan C, Chrzaszcz M, Choi N, Wainwright MS (2010) Chronic upregulation of activated microglia immunoreactive for galectin-3/Mac-2 and nerve growth factor following diffuse axonal injury. J Neuroinflammation 7:32CrossRefPubMedCentralPubMed
40.
Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, van de Lagemaat LN, Smith KA, Ebbert A, Riley ZL, Abajian C, Beckmann CF, Bernard A, Bertagnolli D, Boe AF, Cartagena PM, Chakravarty MM, Chapin M, Chong J, Dalley RA, Daly BD, Dang C, Datta S, Dee N, Dolbeare TA, Faber V, Feng D, Fowler DR (2012) An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489:391–9CrossRefPubMedCentralPubMed
41.
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ (2014) An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex. J Neurosci 34:11929–47CrossRefPubMedCentralPubMed
42.
Gómez-Nicola D, Fransen NL, Suzzi S, Perry VH (2013) Regulation of microglial proliferation during chronic neurodegeneration. J Neurosci 33:2481–93CrossRefPubMed
43.
Cunningham C (2013) Microglia and neurodegeneration: the role of systemic inflammation. Glia 61:71–90CrossRefPubMed
44.
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705CrossRefPubMedCentralPubMed
45.
Lalancette-Hébert M, Swarup V, Beaulieu JM, Bohacek I, Abdelhamid E, Weng YC, Sato S, Kriz J (2012) Galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury. J Neurosci 32:10383–95CrossRefPubMed
46.
Llorens-Martín M, Torres-Alemán I, Trejo JL (2009) Mechanisms mediating brain plasticity: IGF1 and adult hippocampal neurogenesis. Neuroscientist 15:134–48CrossRefPubMed
47.
Elmore MRP, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, Kitazawa M, Matusow B, Nguyen H, West BL, Green KN (2014) Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82:380–97CrossRefPubMedCentralPubMed
48.
Hoehn HJ, Kress Y, Sohn A, Brosnan CF, Bourdon S, Shafit-Zagardo B (2008) Axl-/- mice have delayed recovery and prolonged axonal damage following cuprizone toxicity. Brain Res 1240:1–11CrossRefPubMed
49.
Weinger JG, Brosnan CF, Loudig O, Goldberg MF, Macian F, Arnett HA, Prieto AL, Tsiperson V, Shafit-Zagardo B (2011) Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during Experimental Autoimmune Encephalomyelitis. J Neuroinflammation 8:49CrossRefPubMedCentralPubMed
50.
Weinger JG, Omari KM, Marsden K, Raine CS, Shafit-Zagardo B (2009) Up-regulation of soluble Axl and Mer receptor tyrosine kinases negatively correlates with Gas6 in established multiple sclerosis lesions. Am J Pathol 175:283–93CrossRefPubMedCentralPubMed
51.
52.
Lloyd-Burton SM, York EM, Anwar MA, Vincent AJ, Roskams AJ (2013) SPARC regulates microgliosis and functional recovery following cortical ischemia. J Neurosci 33:4468–81CrossRefPubMed
53.
Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, Botti P, Bacon KB, Feng L (1998) Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci U S A 95:10896–901CrossRefPubMedCentralPubMed
54.
Cho S-H, Sun B, Zhou Y, Kauppinen TM, Halabisky B, Wes P, Ransohoff RM, Gan L (2011) CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J Biol Chem 286:32713–22CrossRefPubMedCentralPubMed
55.
Fuhrmann M, Bittner T, Jung CKE, Burgold S, Page RM, Mitteregger G, Haass C, LaFerla FM, Kretzschmar H, Herms J (2010) Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci 13:411–3CrossRefPubMedCentralPubMed
56.
Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee J-C, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–24CrossRefPubMed
57.
Dénes A, Ferenczi S, Halász J, Kornyei Z, Kovacs KJ (2008) Role of CX3CR1 (fractalkine receptor) in brain damage and inflammation induced by focal cerebral ischemia in mouse. J Cereb Blood Flow Metab 28:1707–21CrossRefPubMed
58.
Biber K, Neumann H, Inoue K, Boddeke HWGM (2007) Neuronal “On” and “Off” signals control microglia. Trends Neurosci 30:596–602CrossRefPubMed
59.
Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, Berkutzki T, Barnett-Itzhaki Z, Bezalel D, Wyss-Coray T, Amit I, Schwartz M (2014) Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346:89–93CrossRefPubMed
60.
Orre M, Kamphuis W, Osborn LM, Melief J, Kooijman L, Huitinga I, Klooster J, Bossers K, Hol EM (2014) Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice. Neurobiol Aging 35:1–14CrossRefPubMed
61.
Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D (1989) Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol 24:173–82CrossRefPubMed
62.
Metadata
Title
Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis
Authors
Inge R Holtman
Divya D Raj
Jeremy A Miller
Wandert Schaafsma
Zhuoran Yin
Nieske Brouwer
Paul D Wes
Thomas Möller
Marie Orre
Willem Kamphuis
Elly M Hol
Erik W G M Boddeke
Bart J L Eggen
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2015
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/s40478-015-0203-5

Other articles of this Issue 1/2015

Acta Neuropathologica Communications 1/2015 Go to the issue

Erratum

Erratum to: Post-mortem brain analyses of the Lothian Birth Cohort 1936: extending lifetime cognitive and brain phenotyping to the level of the synapse

Research

Autoimmune encephalitis in humans: how closely does it reflect multiple sclerosis ?

Research

Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma

Research

Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications

Research

Molecular pathomechanisms and cell-type-specific disease phenotypes of MELAS caused by mutant mitochondrial tRNATrp

Research

Pathogenic aquaporin-4 reactive T cells are sufficient to induce mouse model of neuromyelitis optica