CoChat
Sign Up
Cited by 147Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models

Open access
Sebastian Monasor, Laura, Müller, Stephan A, Colombo, Alessio Vittorio, Tanrioever, Gaye, König, Jasmin, Roth, Stefan, Liesz, Arthur, Berghofer, Anna +9 more·2020·eLife
DOI 10.7554/elife.54083PMC PMC7279888

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Microglial dysfunction is a key pathological feature of Alzheimer's disease (AD), but little is known about proteome-wide changes in microglia during the course of AD and their functional consequences. Here, we performed an in-depth and time-resolved proteomic characterization of microglia in two mouse models of amyloid β (Aβ) pathology, the overexpression APPPS1 and the knock-in APP-NL-G-F (APP-KI) model. We identified a large panel of Microglial Aβ Response Proteins (MARPs) that reflect heterogeneity of microglial alterations during early, middle and advanced stages of Aβ deposition and occur earlier in the APPPS1 mice. Strikingly, the kinetic differences in proteomic profiles correlated with the presence of fibrillar Aβ, rather than dystrophic neurites, suggesting that fibrillar Aβ may trigger the AD-associated microglial phenotype and the observed functional decline. The identified microglial proteomic fingerprints of AD provide a valuable resource for functional studies of novel molecular targets and potential biomarkers for monitoring AD progression or therapeutic efficacy.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.7554/elife.54083

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • THEM6 has been shown to be a microglial Aβ response protein, with increased abundance in the presence of amyloid pathology.

    “THEM6 has been shown to be a microglial Aβ response protein, with increased abundance in the presence of amyloid pathology. 45”

    From Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells (2025) · cites this paper as [45]

    The Results describe proteins whose abundance changes in plaque-associated microglia, and the Discussion describes a broader proteomic response to Aβ deposition. Neither identifies THEM6 or reports its abundance. Searches for “THEM6” and its expanded protein name found no supporting passage in our copy. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 110 · Cited by 147

Part of this paper’s reference list could not be split into single entries.

Research works printed but not linked: 73

  1. Abner EL Neltner JH Jicha GA Patel E Anderson SL Wilcock DM Van Eldik LJ Nelson PT 2018 Diffuse Amyloid-β plaques, neurofibrillary tangles, and the impact of APOE in elderly persons' Brains lacking neuritic amyloid plaques Journal of Alzheimer's Disease 64 1307 1324 10.3233/JAD-180514 30040735 PMC6537103 · DOI
  2. Bacskai BJ Kajdasz ST Christie RH Carter C Games D Seubert P Schenk D Hyman BT 2001 Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy Nature Medicine 7 369 372 10.1038/85525 11231639 · DOI
  3. 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 Journal of Neuroscience 28 4283 4292 10.1523/JNEUROSCI.4814-07.2008 18417708 PMC3844768 · DOI · Paper page
  4. Böttcher C Schlickeiser S Sneeboer MAM Kunkel D Knop A Paza E Fidzinski P Kraus L Snijders GJL Kahn RS Schulz AR Mei HE Hol EM Siegmund B Glauben R Spruth EJ de Witte LD Priller J NBB-Psy 2019 Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry Nature Neuroscience 22 78 90 10.1038/s41593-018-0290-2 30559476 · DOI · Paper page
  5. Boza-Serrano A Ruiz R Sanchez-Varo R García-Revilla J Yang Y Jimenez-Ferrer I Paulus A Wennström M Vilalta A Allendorf D Davila JC Stegmayr J Jiménez S Roca-Ceballos MA Navarro-Garrido V Swanberg M Hsieh CL Real LM Englund E Linse S Leffler H Nilsson UJ Brown GC Gutierrez A Vitorica J Venero JL Deierborg T 2019 Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease Acta Neuropathologica 138 251 273 10.1007/s00401-019-02013-z 31006066 PMC6660511 · DOI · Paper page
  6. Bruderer R Bernhardt OM Gandhi T Miladinović SM Cheng LY Messner S Ehrenberger T Zanotelli V Butscheid Y Escher C Vitek O Rinner O Reiter L 2015 Extending the limits of quantitative proteome profiling with data-independent acquisition and application to acetaminophen-treated three-dimensional liver microtissues Molecular & Cellular Proteomics 14 1400 1410 10.1074/mcp.M114.044305 25724911 PMC4424408 · DOI · Paper page
  7. Calovi S Mut-Arbona P Sperlágh B 2019 Microglia and the purinergic signaling system Neuroscience 405 137 147 10.1016/j.neuroscience.2018.12.021 30582977 · DOI
  8. Cox J Hein MY Luber CA Paron I Nagaraj N Mann M 2014 Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ Molecular & Cellular Proteomics 13 2513 2526 10.1074/mcp.M113.031591 24942700 PMC4159666 · DOI · Paper page
  9. Cummings BJ Su JH Geddes JW Van Nostrand WE Wagner SL Cunningham DD Cotman CW 1992 Aggregation of the amyloid precursor protein within degenerating neurons and dystrophic neurites in Alzheimer's disease Neuroscience 48 763 777 10.1016/0306-4522(92)90265-4 1378573 · DOI · Paper page
  10. Cuyvers E Sleegers K 2016 Genetic variations underlying Alzheimer's disease: evidence from genome-wide association studies and beyond The Lancet Neurology 15 857 868 10.1016/S1474-4422(16)00127-7 27302364 · DOI
  11. D'Andrea MR Cole GM Ard MD 2004 The microglial phagocytic role with specific plaque types in the Alzheimer disease brain Neurobiology of Aging 25 675 683 10.1016/j.neurobiolaging.2003.12.026 15172747 · DOI · Paper page
  12. Dammers C Gremer L Neudecker P Demuth HU Schwarten M Willbold D 2015a Purification and characterization of recombinant N-Terminally Pyroglutamate-Modified Amyloid-β variants and structural analysis by solution NMR spectroscopy PLOS ONE 10 e0139710 10.1371/journal.pone.0139710 26436664 PMC4593648 · DOI
  13. Dammers C Gremer L Reiß K Klein AN Neudecker P Hartmann R Sun N Demuth HU Schwarten M Willbold D 2015b Structural analysis and aggregation propensity of pyroglutamate Aβ(3-40) in aqueous trifluoroethanol PLOS ONE 10 e0143647 10.1371/journal.pone.0143647 26600248 PMC4658145 · DOI
  14. Edison P Donat CK Sastre M 2018 In vivo imaging of glial activation in Alzheimer's disease Frontiers in Neurology 9 625 10.3389/fneur.2018.00625 30131755 PMC6090997 · DOI
  15. Flowers A Bell-Temin H Jalloh A Stevens SM Bickford PC 2017 Proteomic anaysis of aged microglia: shifts in transcription, bioenergetics, and nutrient response Journal of Neuroinflammation 14 96 10.1186/s12974-017-0840-7 28468668 PMC5415769 · DOI
  16. Gjoneska E Pfenning AR Mathys H Quon G Kundaje A Tsai LH Kellis M 2015 Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease Nature 518 365 369 10.1038/nature14252 25693568 PMC4530583 · DOI · Paper page
  17. Götzl JK Brendel M Werner G Parhizkar S Sebastian Monasor L Kleinberger G Colombo AV Deussing M Wagner M Winkelmann J Diehl-Schmid J Levin J Fellerer K Reifschneider A Bultmann S Bartenstein P Rominger A Tahirovic S Smith ST Madore C Butovsky O Capell A Haass C 2019 Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism EMBO Molecular Medicine 11 e9711 10.15252/emmm.201809711 31122931 PMC6554672 · DOI
  18. Grabert K Michoel T Karavolos MH Clohisey S Baillie JK Stevens MP Freeman TC Summers KM McColl BW 2016 Microglial brain region-dependent diversity and selective regional sensitivities to aging Nature Neuroscience 19 504 516 10.1038/nn.4222 26780511 PMC4768346 · DOI · Paper page
  19. Guerreiro R Wojtas A Bras J Carrasquillo M Rogaeva E Majounie E Cruchaga C Sassi C Kauwe JS Younkin S Hazrati L Collinge J Pocock J Lashley T Williams J Lambert JC Amouyel P Goate A Rademakers R Morgan K Powell J St George-Hyslop P Singleton A Hardy J Alzheimer Genetic Analysis Group 2013 TREM2 variants in Alzheimer's disease The New England Journal of Medicine 368 117 127 10.1056/NEJMoa1211851 23150934 PMC3631573 · DOI · Paper page
  20. Guillot-Sestier MV Town T 2013 Innate immunity in Alzheimer's disease: a complex affair CNS & Neurological Disorders Drug Targets 12 593 607 10.2174/1871527311312050008 23574177 PMC3792655 · DOI
  21. Hartlage-Rübsamen M Bluhm A Piechotta A Linnert M Rahfeld J-U Demuth H-U Lues I Kuhn P-H Lichtenthaler S Roßner S Höfling C 2018 Immunohistochemical evidence from APP-Transgenic mice for glutaminyl cyclase as drug target to diminish pE-Abeta formation Molecules 23 924 10.3390/molecules23040924 PMC6017857 29673150 · DOI
  22. Hemonnot AL Hua J Ulmann L Hirbec H 2019 Microglia in Alzheimer disease: well-known targets and new opportunities Frontiers in Aging Neuroscience 11 233 10.3389/fnagi.2019.00233 31543810 PMC6730262 · DOI · Paper page
  23. Holtzman DM Morris JC Goate AM 2011 Alzheimer's disease: the challenge of the second century Science Translational Medicine 3 77sr1 10.1126/scitranslmed.3002369 21471435 PMC3130546 · DOI · Paper page
  24. Huang daW Sherman BT Lempicki RA 2009a Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists Nucleic Acids Research 37 1 13 10.1093/nar/gkn923 19033363 PMC2615629 · DOI · Paper page
  25. Huang daW Sherman BT Lempicki RA 2009b Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources Nature Protocols 4 44 57 10.1038/nprot.2008.211 19131956 · DOI · Paper page
  26. Jansen IE Savage JE Watanabe K Bryois J Williams DM Steinberg S Sealock J Karlsson IK Hägg S Athanasiu L Voyle N Proitsi P Witoelar A Stringer S Aarsland D Almdahl IS Andersen F Bergh S Bettella F Bjornsson S Brækhus A Bråthen G de Leeuw C Desikan RS Djurovic S Dumitrescu L Fladby T Hohman TJ Jonsson PV Kiddle SJ Rongve A Saltvedt I Sando SB Selbæk G Shoai M Skene NG Snaedal J Stordal E Ulstein ID Wang Y White LR Hardy J Hjerling-Leffler J Sullivan PF van der Flier WM Dobson R Davis LK Stefansson H Stefansson K Pedersen NL Ripke S Andreassen OA Posthuma D 2019 Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk Nature Genetics 51 404 413 10.1038/s41588-018-0311-9 30617256 PMC6836675 · DOI · Paper page
  27. Janus C Pearson J McLaurin J Mathews PM Jiang Y Schmidt SD Chishti MA Horne P Heslin D French J Mount HT Nixon RA Mercken M Bergeron C Fraser PE St George-Hyslop P Westaway D 2000 A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease Nature 408 979 982 10.1038/35050110 11140685 · DOI · Paper page
  28. Jay TR Hirsch AM Broihier ML Miller CM Neilson LE Ransohoff RM Lamb BT Landreth GE 2017 Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer's disease The Journal of Neuroscience 37 637 647 10.1523/JNEUROSCI.2110-16.2016 28100745 PMC5242410 · DOI · Paper page
  29. Jonsson T Stefansson H Steinberg S Jonsdottir I Jonsson PV Snaedal J Bjornsson S Huttenlocher J Levey AI Lah JJ Rujescu D Hampel H Giegling I Andreassen OA Engedal K Ulstein I Djurovic S Ibrahim-Verbaas C Hofman A Ikram MA van Duijn CM Thorsteinsdottir U Kong A Stefansson K 2013 Variant of TREM2 associated with the risk of Alzheimer's disease The New England Journal of Medicine 368 107 116 10.1056/NEJMoa1211103 23150908 PMC3677583 · DOI · Paper page
  30. Jordão MJC Sankowski R Brendecke SM Sagar Locatelli G Tai YH Tay TL Schramm E Armbruster S Hagemeyer N Groß O Mai D Çiçek Ö Falk T Kerschensteiner M Grün D Prinz M 2019 Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation Science 363 eaat7554 10.1126/science.aat7554 30679343 · DOI · Paper page
  31. Jung CK Keppler K Steinbach S Blazquez-Llorca L Herms J 2015 Fibrillar amyloid plaque formation precedes microglial activation PLOS ONE 10 e0119768 10.1371/journal.pone.0119768 25799372 PMC4370641 · DOI
  32. Karch CM Goate AM 2015 Alzheimer's disease risk genes and mechanisms of disease pathogenesis Biological Psychiatry 77 43 51 10.1016/j.biopsych.2014.05.006 24951455 PMC4234692 · DOI · Paper page
  33. Klingstedt T Aslund A Simon RA Johansson LB Mason JJ Nyström S Hammarström P Nilsson KP 2011 Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates Organic & Biomolecular Chemistry 9 8356 8370 10.1039/c1ob05637a 22051883 PMC3326384 · DOI
  34. Koellhoffer E McCullough L Ritzel R 2017 Old maids: aging and its impact on microglia function International Journal of Molecular Sciences 18 769 10.3390/ijms18040769 PMC5412353 28379162 · DOI
  35. Lathuilière A Laversenne V Astolfo A Kopetzki E Jacobsen H Stampanoni M Bohrmann B Schneider BL Aebischer P 2016 A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies Brain 139 1587 1604 10.1093/brain/aww036 26956423 · DOI
  36. Liu S Liu Y Hao W Wolf L Kiliaan AJ Penke B Rübe CE Walter J Heneka MT Hartmann T Menger MD Fassbender K 2012 TLR2 is a primary receptor for Alzheimer's amyloid β peptide to trigger neuroinflammatory activation The Journal of Immunology 188 1098 1107 10.4049/jimmunol.1101121 22198949 · DOI · Paper page
  37. Mathys H Adaikkan C Gao F Young JZ Manet E Hemberg M De Jager PL Ransohoff RM Regev A Tsai LH 2017 Temporal tracking of microglia activation in neurodegeneration at Single-Cell resolution Cell Reports 21 366 380 10.1016/j.celrep.2017.09.039 29020624 PMC5642107 · DOI · Paper page
  38. Mawuenyega KG Sigurdson W Ovod V Munsell L Kasten T Morris JC Yarasheski KE Bateman RJ 2010 Decreased clearance of CNS beta-amyloid in Alzheimer's disease Science 330 1774 10.1126/science.1197623 21148344 PMC3073454 · DOI · Paper page
  39. McDonald CL Hennessy E Rubio-Araiz A Keogh B McCormack W McGuirk P Reilly M Lynch MA 2016 Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer's disease Brain, Behavior, and Immunity 58 191 200 10.1016/j.bbi.2016.07.143 27422717 · DOI · Paper page
  40. McQuade A Blurton-Jones M 2019 Microglia in Alzheimer's disease: exploring how genetics and phenotype influence risk Journal of Molecular Biology 431 1805 1817 10.1016/j.jmb.2019.01.045 30738892 PMC6475606 · DOI · Paper page
  41. Mildner A Huang H Radke J Stenzel W Priller J 2017 P2Y12 receptor is expressed on human microglia under physiological conditions throughout development and is sensitive to neuroinflammatory diseases Glia 65 375 387 10.1002/glia.23097 27862351 · DOI · Paper page
  42. Morgan D Diamond DM Gottschall PE Ugen KE Dickey C Hardy J Duff K Jantzen P DiCarlo G Wilcock D Connor K Hatcher J Hope C Gordon M Arendash GW 2000 A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease Nature 408 982 985 10.1038/35050116 11140686 · DOI
  43. Mrdjen D Pavlovic A Hartmann FJ Schreiner B Utz SG Leung BP Lelios I Heppner FL Kipnis J Merkler D Greter M Becher B 2018 High-Dimensional Single-Cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease Immunity 48 380 395 10.1016/j.immuni.2018.01.011 29426702 · DOI · Paper page
  44. Nicoll JA Barton E Boche D Neal JW Ferrer I Thompson P Vlachouli C Wilkinson D Bayer A Games D Seubert P Schenk D Holmes C 2006 Abeta species removal after abeta42 immunization Journal of Neuropathology and Experimental Neurology 65 1040 1048 10.1097/01.jnen.0000240466.10758.ce 17086100 · DOI · Paper page
  45. Nyström S Psonka-Antonczyk KM Ellingsen PG Johansson LB Reitan N Handrick S Prokop S Heppner FL Wegenast-Braun BM Jucker M Lindgren M Stokke BT Hammarström P Nilsson KP 2013 Evidence for age-dependent in vivo conformational rearrangement within aβ amyloid deposits ACS Chemical Biology 8 1128 1133 10.1021/cb4000376 23521783 · DOI
  46. Orre M Kamphuis W Osborn LM Jansen AHP Kooijman L Bossers K Hol EM 2014a Isolation of Glia from Alzheimer's mice reveals inflammation and dysfunction Neurobiology of Aging 35 2746 2760 10.1016/j.neurobiolaging.2014.06.004 25002035 · DOI · Paper page
  47. Orre M Kamphuis W Osborn LM Melief J Kooijman L Huitinga I Klooster J Bossers K Hol EM 2014b Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice Neurobiology of Aging 35 1 14 10.1016/j.neurobiolaging.2013.07.008 23954174 · DOI
  48. Parhizkar S Arzberger T Brendel M Kleinberger G Deussing M Focke C Nuscher B Xiong M Ghasemigharagoz A Katzmarski N Krasemann S Lichtenthaler SF Müller SA Colombo A Monasor LS Tahirovic S Herms J Willem M Pettkus N Butovsky O Bartenstein P Edbauer D Rominger A Ertürk A Grathwohl SA Neher JJ Holtzman DM Meyer-Luehmann M Haass C 2019 Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE Nature Neuroscience 22 191 204 10.1038/s41593-018-0296-9 30617257 PMC6417433 · DOI · Paper page
  49. Perez-Riverol Y Csordas A Bai J Bernal-Llinares M Hewapathirana S Kundu DJ Inuganti A Griss J Mayer G Eisenacher M Pérez E Uszkoreit J Pfeuffer J Sachsenberg T Yilmaz S Tiwary S Cox J Audain E Walzer M Jarnuczak AF Ternent T Brazma A Vizcaíno JA 2019 The PRIDE database and related tools and resources in 2019: improving support for quantification data Nucleic Acids Research 47 D442 D450 10.1093/nar/gky1106 30395289 PMC6323896 · DOI
  50. Radde R Bolmont T Kaeser SA Coomaraswamy J Lindau D Stoltze L Calhoun ME Jäggi F Wolburg H Gengler S Haass C Ghetti B Czech C Hölscher C Mathews PM Jucker M 2006 Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology EMBO Reports 7 940 946 10.1038/sj.embor.7400784 16906128 PMC1559665 · DOI · Paper page
  51. Rangaraju S Dammer EB Raza SA Gao T Xiao H Betarbet R Duong DM Webster JA Hales CM Lah JJ Levey AI Seyfried NT 2018 Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer's disease-related proteins Molecular Neurodegeneration 13 34 10.1186/s13024-018-0266-4 29954413 PMC6025801 · DOI
  52. Rappsilber J Ishihama Y Mann M 2003 Stop and go extraction tips for matrix-assisted laser desorption/ionization, Nanoelectrospray, and LC/MS sample pretreatment in proteomics Analytical Chemistry 75 663 670 10.1021/ac026117i 12585499 · DOI
  53. Rasmussen J Mahler J Beschorner N Kaeser SA Häsler LM Baumann F Nyström S Portelius E Blennow K Lashley T Fox NC Sepulveda-Falla D Glatzel M Oblak AL Ghetti B Nilsson KPR Hammarström P Staufenbiel M Walker LC Jucker M 2017 Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease PNAS 114 13018 13023 10.1073/pnas.1713215114 29158413 PMC5724274 · DOI
  54. Reddy PH Manczak M Zhao W Nakamura K Bebbington C Yarranton G Mao P 2009 Granulocyte-macrophage colony-stimulating factor antibody suppresses microglial activity: implications for anti-inflammatory effects in Alzheimer's disease and multiple sclerosis Journal of Neurochemistry 111 1514 1528 10.1111/j.1471-4159.2009.06432.x 19840215 PMC2796704 · DOI
  55. Sadleir KR Kandalepas PC Buggia-Prévot V Nicholson DA Thinakaran G Vassar R 2016 Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased aβ generation in Alzheimer's disease Acta Neuropathologica 132 235 256 10.1007/s00401-016-1558-9 26993139 PMC4947125 · DOI · Paper page
  56. Saido TC 1998 Alzheimer's disease as proteolytic disorders: anabolism and catabolism of beta-amyloid Neurobiology of Aging 19 S69 S75 10.1016/S0197-4580(98)00033-5 9562472 · DOI
  57. Scholtzova H Kascsak RJ Bates KA Boutajangout A Kerr DJ Meeker HC Mehta PD Spinner DS Wisniewski T 2009 Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology Journal of Neuroscience 29 1846 1854 10.1523/JNEUROSCI.5715-08.2009 19211891 PMC2699573 · DOI · Paper page
  58. Sevigny J Chiao P Bussière T Weinreb PH Williams L Maier M Dunstan R Salloway S Chen T Ling Y O'Gorman J Qian F Arastu M Li M Chollate S Brennan MS Quintero-Monzon O Scannevin RH Arnold HM Engber T Rhodes K Ferrero J Hang Y Mikulskis A Grimm J Hock C Nitsch RM Sandrock A 2016 The antibody aducanumab reduces aβ plaques in Alzheimer's disease Nature 537 50 56 10.1038/nature19323 27582220 · DOI · Paper page
  59. Shi Y Holtzman DM 2018 Interplay between innate immunity and Alzheimer disease: apoe and TREM2 in the spotlight Nature Reviews Immunology 18 759 772 10.1038/s41577-018-0051-1 30140051 PMC6425488 · DOI · Paper page
  60. Solito E Sastre M 2012 Microglia function in Alzheimer's disease Frontiers in Pharmacology 3 14 10.3389/fphar.2012.00014 22363284 PMC3277080 · DOI
  61. Thygesen C Ilkjær L Kempf SJ Hemdrup AL von Linstow CU Babcock AA Darvesh S Larsen MR Finsen B 2018 Diverse protein profiles in CNS myeloid cells and CNS tissue from lipopolysaccharide- and vehicle-injected APPSWE/PS1ΔE9 transgenic mice implicate cathepsin Z in Alzheimer's disease Frontiers in Cellular Neuroscience 12 397 10.3389/fncel.2018.00397 30459560 PMC6232379 · DOI
  62. Tusher VG Tibshirani R Chu G 2001 Significance analysis of microarrays applied to the ionizing radiation response PNAS 98 5116 5121 10.1073/pnas.091062498 11309499 PMC33173 · DOI · Paper page
  63. Tyanova S Temu T Sinitcyn P Carlson A Hein MY Geiger T Mann M Cox J 2016 The perseus computational platform for comprehensive analysis of (prote)omics data Nature Methods 13 731 740 10.1038/nmeth.3901 27348712 · DOI
  64. Ulrich JD Ulland TK Mahan TE Nyström S Nilsson KP Song WM Zhou Y Reinartz M Choi S Jiang H Stewart FR Anderson E Wang Y Colonna M Holtzman DM 2018 ApoE facilitates the microglial response to amyloid plaque pathology Journal of Experimental Medicine 215 1047 1058 10.1084/jem.20171265 29483128 PMC5881464 · DOI · Paper page
  65. Wang Y Cella M Mallinson K Ulrich JD Young KL Robinette ML Gilfillan S Krishnan GM Sudhakar S Zinselmeyer BH Holtzman DM Cirrito JR Colonna M 2015 TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model Cell 160 1061 1071 10.1016/j.cell.2015.01.049 25728668 PMC4477963 · DOI · Paper page
  66. Wilcock DM Rojiani A Rosenthal A Levkowitz G Subbarao S Alamed J Wilson D Wilson N Freeman MJ Gordon MN Morgan D 2004 Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition Journal of Neuroscience 24 6144 6151 10.1523/JNEUROSCI.1090-04.2004 15240806 PMC6729674 · DOI
  67. Wildsmith KR Holley M Savage JC Skerrett R Landreth GE 2013 Evidence for impaired amyloid β clearance in Alzheimer's disease Alzheimer's Research & Therapy 5 33 10.1186/alzrt187 23849219 PMC3978761 · DOI
  68. Wiśniewski JR Zougman A Nagaraj N Mann M 2009 Universal sample preparation method for proteome analysis Nature Methods 6 359 362 10.1038/nmeth.1322 19377485 · DOI · Paper page
  69. Yamasaki A Eimer S Okochi M Smialowska A Kaether C Baumeister R Haass C Steiner H 2006 The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase Journal of Neuroscience 26 3821 3828 10.1523/JNEUROSCI.5354-05.2006 16597736 PMC6674133 · DOI
  70. Yin Z Raj D Saiepour N Van Dam D Brouwer N Holtman IR Eggen BJL Möller T Tamm JA Abdourahman A Hol EM Kamphuis W Bayer TA De Deyn PP Boddeke E 2017 Immune hyperreactivity of aβ plaque-associated microglia in Alzheimer's disease Neurobiology of Aging 55 115 122 10.1016/j.neurobiolaging.2017.03.021 28434692 · DOI · Paper page
  71. Yuan P Condello C Keene CD Wang Y Bird TD Paul SM Luo W Colonna M Baddeley D Grutzendler J 2016 TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy Neuron 92 252 264 10.1016/j.neuron.2016.09.016 27710785 · DOI · Paper page
  72. Zhou Y Song WM Andhey PS Swain A Levy T Miller KR Poliani PL Cominelli M Grover S Gilfillan S Cella M Ulland TK Zaitsev K Miyashita A Ikeuchi T Sainouchi M Kakita A Bennett DA Schneider JA Nichols MR Beausoleil SA Ulrich JD Holtzman DM Artyomov MN Colonna M 2020 Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease Nature Medicine 26 131 142 10.1038/s41591-019-0695-9 31932797 PMC6980793 · DOI · Paper page
  73. Zuroff L Daley D Black KL Koronyo-Hamaoui M 2017 Clearance of cerebral aβ in Alzheimer's disease: reassessing the role of microglia and monocytes Cellular and Molecular Life Sciences 74 2167 2201 10.1007/s00018-017-2463-7 28197669 PMC5425508 · DOI

Authors
Sebastian Monasor, L., Müller, S. A., Colombo, A. V., Tanrioever, G., König, J., Roth, S., Liesz, A., Berghofer, A., Piechotta, A., Prestel, M., Saito, T., Saido, T. C., Herms, J., Willem, M., Haass, C., Lichtenthaler, S. F., & Tahirovic, S.
Affiliations
  • German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
  • German Center for Neurodegenerative Diseases (DE)
  • German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
  • Institut für Schlaganfall- und Demenzforschung (DE)
  • Munich Cluster for Systems Neurology (DE)
  • TUM Klinikum (DE)
  • Fraunhofer Institute for Cell Therapy and Immunology (DE)
  • RIKEN Center for Brain Science (JP)
  • Ludwig-Maximilians-Universität München (DE)
Corresponding author
Lichtenthaler, Stefan F
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2020-06-08
Volume
9
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.54083
PMC
PMC7279888
OpenAlex
W3034168187
Cited by
147
References
110
Citations by year
2026: 9 · 2025: 28 · 2024: 24 · 2023: 21 · 2022: 20 · 2021: 36 · 2020: 9
FWCI
8.32
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
  • Publikationsdatenbank der Fraunhofer-Gesellschaft (Fraunhofer-Gesellschaft) (submittedVersion, other-oa)
  • DZNE Pub (submittedVersion, cc-by)
  • Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
Funders
  • Alzheimer Forschung Initiative (18014)
  • Deutsche Forschungsgemeinschaft (EXC 2145 SyNergy ID 390857198, Koselleck Project HA1737/16-1)
  • H2020 European Research Council (ERC-StG 802305)
  • Helmholtz-Gemeinschaft (ZT-0027)
  • Bundesministerium für Bildung und Forschung (JPND PMG-AD, CLINSPECT-M)
  • NCL Foundation (01133)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, microglial dysfunction, amyloid-beta, fibrillar amyloid-beta, APP/PS1 mice, APP knock-in mice, dystrophic neurites, disease progression, biomarkers, mouse model
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Female, Male, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Proteome, Mice, Gene Knock-In Techniques

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review