Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model

Abstract

TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of β-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2 ko ) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2 ko mice, with Trem2 -deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2 ko females at 6–7 months; but by 12 or 19–22 months of age, it was notably diminished in female and male PS2APP;Trem2 ko mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2 ko brains, and the Aβ42:Aβ40 ratio was elevated. The amount of soluble, fibrillar Aβ oligomers also increased in PS2APP;Trem2 ko hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2 ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2 ko mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of Trem2 deficiency than amyloid plaque load, suggesting that the microglial packing of Aβ into dense plaque is an important neuroprotective activity. SIGNIFICANCE STATEMENT Genetic studies indicate that TREM2 gene mutations confer increased Alzheimer's disease (AD) risk. We studied the effects of Trem2 deletion in the PS2APP mouse AD model, in which overproduction of Aβ peptide leads to amyloid plaque formation and associated neuritic dystrophy. Interestingly, neuritic dystrophies were intensified in the brains of Trem2 -deficient mice, despite these mice displaying reduced plaque accumulation at later ages (12–22 months). Microglial clustering around plaques was impaired, plaques were more diffuse, and the Aβ42:Aβ40 ratio and amount of soluble, fibrillar Aβ oligomers were elevated in Trem2 -deficient brains. These results suggest that the Trem2-dependent compaction of Aβ into dense plaques is a protective microglial activity, limiting the exposure of neurons to toxic Aβ species.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 98

1. 1.

   Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P (2003 ) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–590.

   Not in our library10.1046/j.1471-4159.2003.01879.x

2. 2.

   Bacioglu M, Maia LF, Preische O, Schelle J, Apel A, Kaeser SA, Schweighauser M, Eninger T, Lambert M, Pilotto A, Shimshek DR, Neumann U, Kahle PJ, Staufenbiel M, Neumann M, Maetzler W, Kuhle J, Jucker M (2016 ) Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases. Neuron 91:56–66.

   Not in our library10.1016/j.neuron.2016.05.018

3. 3.
   TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy · 2017

   No notice
4. 4.

   Berger H, Wodarz A, Borchers A (2017 ) PTK7 faces the wnt in development and disease. Front Cell Dev Biol 5:31.

   Not in our library10.3389/fcell.2017.00031

5. 5.

   Boerboom D, White LD, Dalle S, Courty J, Richards JS (2006 ) Dominant-stable beta-catenin expression causes cell fate alterations and wnt signaling antagonist expression in a murine granulosa cell tumor model. Cancer Res 66:1964–1973.

   Not in our library10.1158/0008-5472.can-05-3493

6. 6.

   Bouchon A, Hernández-Munain C, Cella M, Colonna M (2001 ) A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J Exp Med 194:1111–1122.

   Not in our library10.1084/jem.194.8.1111

7. 7.

   Buchman JJ, Durak O, Tsai LH (2011 ) ASPM regulates wnt signaling pathway activity in the developing brain. Genes Dev 25:1909–1914.

   Not in our library10.1101/gad.16830211

8. 8.

   Busby V, Goossens S, Nowotny P, Hamilton G, Smemo S, Harold D, Turic D, Jehu L, Myers A, Womick M, Woo D, Compton D, Doil LM, Tacey KM, Lau KF, Al-Saraj S, Killick R, Pickering-Brown S, Moore P, Hollingworth P, et al (2004 ) Alpha-T-catenin is expressed in human brain and interacts with the wnt signaling pathway but is not responsible for linkage to chromosome 10 in Alzheimer's disease. Neuromolecular Med 5:133–146.

   Not in our library10.1385/nmm:5:2:133

9. 9.

   Campbell SK, Switzer RC, Martin TL (1987 ) Alzheimer's plaques and tangles: a controlled and enhanced silver staining method. Soc Neuroscience Abstr 13:678.

   Not in our library

10. 10.

    Cella M, Buonsanti C, Strader C, Kondo T, Salmaggi A, Colonna M (2003 ) Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J Exp Med 198:645–651.

    Not in our library10.1084/jem.20022220

11. 11.

    Condello C, Yuan P, Schain A, Grutzendler J (2015 ) Microglia constitute a barrier that prevents neurotoxic protofibrillar Abeta42 hotspots around plaques. Nat Commun 6:6176.

    Not in our library10.1038/ncomms7176

12. 12.

    D'Amore JD, Kajdasz ST, McLellan ME, Bacskai BJ, Stern EA, Hyman BT (2003 ) In vivo multiphoton imaging of a transgenic mouse model of Alzheimer disease reveals marked thioflavine-S-associated alterations in neurite trajectories. J Neuropathol Exp Neurol 62:137–145.

    Not in our library10.1093/jnen/62.2.137

13. 13.

    Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I (2018 ) Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173:1073–1081.

    Not in our library10.1016/j.cell.2018.05.003

14. 14.

    de Olmos JS, Beltramino CA, de Olmos de Lorenzo S (1994 ) Use of an amino-cupric-silver technique for the detection of early and semiacute neuronal degeneration caused by neurotoxicants, hypoxia, and physical trauma. Neurotoxicol Teratol 16:545–561.

    Not in our library10.1016/0892-0362(94)90033-7

15. 15.

    Devotta A, Hong CS, Saint-Jeannet JP (2018 ) Dkk2 promotes neural crest specification by activating Wnt/beta-catenin signaling in a GSK3beta independent manner. Elife 7:e34404.

    Not in our library10.7554/elife.34404

16. 16.

    Diep DB, Hoen N, Backman M, Machon O, Krauss S (2004 ) Characterisation of the wnt antagonists and their response to conditionally activated wnt signalling in the developing mouse forebrain. Brain Res Dev Brain Res 153:261–270.

    Not in our library10.1016/j.devbrainres.2004.09.008

17. 17.

    Diks SH, Bink RJ, van de Water S, Joore J, van Rooijen C, Verbeek FJ, den Hertog J, Peppelenbosch MP, Zivkovic D (2006 ) The novel gene asb11: a regulator of the size of the neural progenitor compartment. J Cell Biol 174:581–592.

    Not in our library10.1083/jcb.200601081

18. 18.

    Dunn KW, Kamocka MM, McDonald JH (2011 ) A practical guide to evaluating colocalization in biological microscopy. Am J Physiol Cell Physiol 300:C723–C742.

    Not in our library10.1152/ajpcell.00462.2010

19. 19.

    Focke C, Blume T, Zott B, Shi Y, Deussing M, Peters F, Schmidt C, Kleinberger G, Lindner S, Gildehaus FJ, Beyer L, von Ungern-Sternberg B, Bartenstein P, Ozmen L, Baumann K, Dorostkar MM, Haass C, Adelsberger H, Herms J, Rominger A, et al (2019 ) Early and longitudinal microglial activation but not amyloid accumulation predicts cognitive outcome in PS2APP mice. J Nucl Med 60:548–554.

    Not in our library10.2967/jnumed.118.217703

20. 20.

    Fonseca MI, Zhou J, Botto M, Tenner AJ (2004 ) Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J Neurosci 24:6457–6465.

    Not in our library10.1523/jneurosci.0901-04.2004

21. 21.

    Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA, Cao Y, Lee SH, Haddick PC, Ngu H, Modrusan Z, Larson JL, Kaminker JS, van der Brug MP, Hansen DV (2018 ) Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer's disease not evident in mouse models. Cell Rep 22:832–847.

    Not in our library10.1016/j.celrep.2017.12.066

22. 22.

    Gage PJ, Qian M, Wu D, Rosenberg KI (2008 ) The canonical wnt signaling antagonist DKK2 is an essential effector of PITX2 function during normal eye development. Dev Biol 317:310–324.

    Not in our library10.1016/j.ydbio.2008.02.030

23. 23.

    Gowrishankar S, Yuan P, Wu Y, Schrag M, Paradise S, Grutzendler J, De Camilli P, Ferguson SM (2015 ) Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer's disease amyloid plaques. Proc Natl Acad Sci U S A 112:E3699–E3708.

    Not in our library10.1073/pnas.1510329112

24. 24.
    New insights into the role of TREM2 in Alzheimer’s disease · 2018

    No notice
25. 25.

    Griciuc A, Patel S, Federico AN, Choi SH, Innes BJ, Oram MK, Cereghetti G, McGinty D, Anselmo A, Sadreyev RI, Hickman SE, El Khoury J, Colonna M, Tanzi RE (2019 ) TREM2 acts downstream of CD33 in modulating microglial pathology in Alzheimer's disease. Neuron 103:820–835.e7.

    Not in our library10.1016/j.neuron.2019.06.010

26. 26.

    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, et al (2013 ) TREM2 variants in Alzheimer's disease. N Engl J Med 368:117–127.

    Not in our library10.1056/nejmoa1211851

27. 27.

    Haass C, Selkoe DJ (2007 ) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112.

    Not in our library10.1038/nrm2101

28. 28.

    Hamelin L, Lagarde J, Dorothée G, Leroy C, Labit M, Comley RA, de Souza LC, Corne H, Dauphinot L, Bertoux M, Dubois B, Gervais P, Colliot O, Potier MC, Bottlaender M, Sarazin M (2016 ) Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging. Brain 139:1252–1264.

    Not in our library10.1093/brain/aww017

29. 29.

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

    Not in our library10.1083/jcb.201709069

30. 30.

    He Z, Guo JL, McBride JD, Narasimhan S, Kim H, Changolkar L, Zhang B, Gathagan RJ, Yue C, Dengler C, Stieber A, Nitla M, Coulter DA, Abel T, Brunden KR, Trojanowski JQ, Lee VM (2018 ) Amyloid-beta plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 24:29–38.

    Not in our library10.1038/nm.4443

31. 31.

    Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, et al (2015 ) Neuroinflammation in Alzheimer's disease. Lancet Neurol 14:388–405.

    Not in our library10.1016/s1474-4422(15)70016-5

32. 32.

    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B (2016 ) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352:712–716.

    Not in our library10.1126/science.aad8373

33. 33.

    Hsieh JC, Kodjabachian L, Rebbert ML, Rattner A, Smallwood PM, Samos CH, Nusse R, Dawid IB, Nathans J (1999 ) A new secreted protein that binds to wnt proteins and inhibits their activities. Nature 398:431–436.

    Not in our library10.1038/18899

34. 34.

    Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, Bullido MJ, Carter C, Clerici M, Cosby SL, Del Tredici K, Field H, Fulop T, Grassi C, Griffin WS, Haas J, Hudson AP, Kamer AR, Kell DB, Licastro F, et al (2016 ) Microbes and Alzheimer's disease. J Alzheimers Dis 51:979–984.

    Not in our library10.3233/jad-160152

35. 35.

    Jack CR Jr, Wiste HJ, Schwarz CG, Lowe VJ, Senjem ML, Vemuri P, Weigand SD, Therneau TM, Knopman DS, Gunter JL, Jones DT, Graff-Radford J, Kantarci K, Roberts RO, Mielke MM, Machulda MM, Petersen RC (2018 ) Longitudinal tau PET in ageing and Alzheimer's disease. Brain 141:1517–1528.

    Not in our library10.1093/brain/awy059

36. 36.

    Jacobs HI, Hedden T, Schultz AP, Sepulcre J, Perea RD, Amariglio RE, Papp KV, Rentz DM, Sperling RA, Johnson KA (2018 ) Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals. Nat Neurosci 21:424–431.

    Not in our library10.1038/s41593-018-0070-z

37. 37.

    Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, Xu G, Margevicius D, Karlo JC, Sousa GL, Cotleur AC, Butovsky O, Bekris L, Staugaitis SM, Leverenz JB, Pimplikar SW, Landreth GE, Howell GR, Ransohoff RM, Lamb BT (2015 ) TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med 212:287–295.

    Not in our library10.1084/jem.20142322

38. 38.

    Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE, Ransohoff RM, Lamb BT, Landreth GE (2017a ) Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer's disease. J Neurosci 37:637–647.

    Not in our library10.1523/jneurosci.2110-16.2016

39. 39.
    TREM2 in Neurodegenerative Diseases · 2017

    No notice
40. 40.

    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, et al (2013 ) Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med 368:107–116.

    Not in our library10.1056/nejmoa1211103

41. 41.

    Kallop DY, Meilandt WJ, Gogineni A, Easley-Neal C, Wu T, Jubb AM, Yaylaoglu M, Shamloo M, Tessier-Lavigne M, Scearce-Levie K, Weimer RM (2014 ) A death receptor 6-amyloid precursor protein pathway regulates synapse density in the mature CNS but does not contribute to Alzheimer's disease-related pathophysiology in murine models. J Neurosci 34:6425–6437.

    Not in our library10.1523/jneurosci.4963-13.2014

42. 42.

    Kang SS, Kurti A, Baker KE, Liu CC, Colonna M, Ulrich JD, Holtzman DM, Bu G, Fryer JD (2018 ) Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal. Hum Mol Genet 27:211–223.

    Not in our library10.1093/hmg/ddx366

43. 43.

    Karasawa T, Yokokura H, Kitajewski J, Lombroso PJ (2002 ) Frizzled-9 is activated by wnt-2 and functions in Wnt/beta-catenin signaling. J Biol Chem 277:37479–37486.

    Not in our library10.1074/jbc.m205658200

44. 44.

    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I (2017 ) A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169:1276–1290.e17.

    Not in our library10.1016/j.cell.2017.05.018

45. 45.

    Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP, Gattringer T, Barro C, Kappos L, Comabella M, Fazekas F, Petzold A, Blennow K, Zetterberg H, Kuhle J (2018 ) Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol 14:577–589.

    Not in our library10.1038/s41582-018-0058-z

46. 46.

    Kim J, Eltorai AE, Jiang H, Liao F, Verghese PB, Kim J, Stewart FR, Basak JM, Holtzman DM (2012 ) Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of abeta amyloidosis. J Exp Med 209:2149–2156.

    Not in our library10.1084/jem.20121274

47. 47.

    Klein WL (2002 ) Abeta toxicity in Alzheimer's disease: globular oligomers (ADDLs) as new vaccine and drug targets. Neurochem Int 41:345–352.

    Not in our library10.1016/s0197-0186(02)00050-5

48. 48.

    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.

    Not in our library10.1093/jnen/61.9.797

49. 49.

    Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O'Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, et al (2017 ) The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47:566–581.e9.

    Not in our library10.1016/j.immuni.2017.08.008

50. 50.

    Krstic D, Knuesel I (2013 ) The airbag problem—a potential culprit for bench-to-bedside translational efforts: relevance for Alzheimer's disease. Acta Neuropathol Commun 1:62.

    Not in our library10.1186/2051-5960-1-62

51. 51.

    Lai JP, Oseini AM, Moser CD, Yu C, Elsawa SF, Hu C, Nakamura I, Han T, Aderca I, Isomoto H, Garrity-Park MM, Shire AM, Li J, Sanderson SO, Adjei AA, Fernandez-Zapico ME, Roberts LR (2010 ) The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent wnt activation. Hepatology 52:1680–1689.

    Not in our library10.1002/hep.23848

52. 52.
    voom: precision weights unlock linear model analysis tools for RNA-seq read counts · 2014

    No notice
53. 53.

    Le Pichon CE, Dominguez SL, Solanoy H, Ngu H, Lewin-Koh N, Chen M, Eastham-Anderson J, Watts R, Scearce-Levie K (2013 ) EGFR inhibitor erlotinib delays disease progression but does not extend survival in the SOD1 mouse model of ALS. PLoS One 8:e62342.

    Not in our library10.1371/journal.pone.0062342

54. 54.
    High‐affinity interactions and signal transduction between Aβ oligomers and TREM2 · 2018

    No notice
55. 55.

    Leyns CE, Ulrich JD, Finn MB, Stewart FR, Koscal LJ, Remolina Serrano J, Robinson GO, Anderson E, Colonna M, Holtzman DM (2017 ) TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A 114:11524–11529.

    Not in our library10.1073/pnas.1710311114

56. 56.

    Leyns CE, Gratuze M, Narasimhan S, Jain N, Koscal LJ, Jiang H, Manis M, Colonna M, Lee VM, Ulrich JD, Holtzman DM (2019 ) TREM2 function impedes tau seeding in neuritic plaques. Nat Neurosci 22:1217–1222.

    Not in our library10.1038/s41593-019-0433-0

57. 57.

    Lin Z, Gao C, Ning Y, He X, Wu W, Chen YG (2008 ) The pseudoreceptor BMP and activin membrane-bound inhibitor positively modulates Wnt/beta-catenin signaling. J Biol Chem 283:33053–33058.

    Not in our library10.1074/jbc.m804039200

58. 58.
    Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 · 2014

    No notice
59. 59.

    Mao B, Niehrs C (2003 ) Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene 302:179–183.

    Not in our library10.1016/s0378-1119(02)01106-x

60. 60.

    Mazaheri F, Snaidero N, Kleinberger G, Madore C, Daria A, Werner G, Krasemann S, Capell A, Trümbach D, Wurst W, Brunner B, Bultmann S, Tahirovic S, Kerschensteiner M, Misgeld T, Butovsky O, Haass C (2017 ) TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep 18:1186–1198.

    Not in our library10.15252/embr.201743922

61. 61.

    Meilandt WJ, Maloney JA, Imperio J, Lalehzadeh G, Earr T, Crowell S, Bainbridge TW, Lu Y, Ernst JA, Fuji RN, Atwal JK (2019 ) Characterization of the selective in vitro and in vivo binding properties of crenezumab to oligomeric Aβ. Alzheimers Res Ther 11:97.

    Not in our library10.1186/s13195-019-0553-5

62. 62.
    PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools · 2018

    No notice
63. 63.
    Inconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer's Disease · 2014

    No notice
64. 64.
    Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology · 2016

    No notice
65. 65.

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

    Not in our library10.1016/j.neurobiolaging.2014.06.004

66. 66.

    Ozmen L, Albientz A, Czech C, Jacobsen H (2009 ) Expression of transgenic APP mRNA is the key determinant for beta-amyloid deposition in PS2APP transgenic mice. Neurodegener Dis 6:29–36.

    Not in our library10.1159/000170884

67. 67.

    Paloneva J, Mandelin J, Kiialainen A, Bohling T, Prudlo J, Hakola P, Haltia M, Konttinen YT, Peltonen L (2003 ) DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J Exp Med 198:669–675.

    Not in our library10.1084/jem.20030027

68. 68.

    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, et al (2019 ) Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci 22:191–204.

    Not in our library10.1038/s41593-018-0296-9

69. 69.

    Park J, Wetzel I, Marriott I, Dréau D, D'Avanzo C, Kim DY, Tanzi RE, Cho H (2018 ) A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer's disease. Nat Neurosci 21:941–951.

    Not in our library10.1038/s41593-018-0175-4

70. 70.

    Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S, Colonna M (2015 ) TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Invest 125:2161–2170.

    Not in our library10.1172/jci77983

71. 71.
    Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease · 2015

    No notice
72. 72.

    Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B, Lemere CA (2017 ) Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med 9:eaaf6295.

    Not in our library10.1126/scitranslmed.aaf6295

73. 73.

    Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, West BL, Green KN (2016 ) Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139:1265–1281.

    Not in our library10.1093/brain/aww016

74. 74.

    Spires TL, Hyman BT (2004 ) Neuronal structure is altered by amyloid plaques. Rev Neurosci 15:267–278.

    Not in our library10.1515/revneuro.2004.15.4.267

75. 75.

    Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT (2005 ) Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci 25:7278–7287.

    Not in our library10.1523/jneurosci.1879-05.2005

76. 76.
    Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses · 2016

    No notice
77. 77.

    Switzer RC 3rd (2000 ) Application of silver degeneration stains for neurotoxicity testing. Toxicol Pathol 28:70–83.

    Not in our library10.1177/019262330002800109

78. 78.

    Switzer RC, Campbell SK, Murdock TM (1993 ) A histologic method for staining Alzheimer pathology. U.S. Patent 5192688.

    Not in our library

79. 79.

    Tee JM, Sartori da Silva MA, Rygiel AM, Muncan V, Bink R, van den Brink GR, van Tijn P, Zivkovic D, Kodach LL, Guardavaccaro D, Diks SH, Peppelenbosch MP (2012 ) asb11 is a regulator of embryonic and adult regenerative myogenesis. Stem Cells Dev 21:3091–3103.

    Not in our library10.1089/scd.2012.0123

80. 80.

    Tomic JL, Pensalfini A, Head E, Glabe CG (2009 ) Soluble fibrillar oligomer levels are elevated in Alzheimer's disease brain and correlate with cognitive dysfunction. Neurobiol Dis 35:352–358.

    Not in our library10.1016/j.nbd.2009.05.024

81. 81.

    Tsai J, Grutzendler J, Duff K, Gan WB (2004 ) Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 7:1181–1183.

    Not in our library10.1038/nn1335

82. 82.

    Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M, Piccio L, Hernandez M, Colonna M (2006 ) Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 177:3520–3524.

    Not in our library10.4049/jimmunol.177.6.3520

83. 83.

    Ulland TK, Colonna M (2018 ) TREM2: a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 14:667–675.

    Not in our library10.1038/s41582-018-0072-1

84. 84.

    Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A, Beatty WL, Loboda AA, Zhou Y, Cairns NJ, Kambal A, Loginicheva E, Gilfillan S, Cella M, Virgin HW, Unanue ER, Wang Y, Artyomov MN, Holtzman DM, Colonna M (2017 ) TREM2 maintains microglial metabolic fitness in Alzheimer's disease. Cell 170:649–663.e13.

    Not in our library10.1016/j.cell.2017.07.023

85. 85.

    Ulrich JD, Ulland TK, Colonna M, Holtzman DM (2017 ) Elucidating the role of TREM2 in Alzheimer's disease. Neuron 94:237–248.

    Not in our library10.1016/j.neuron.2017.02.042

86. 86.

    Wang A, Das P, Switzer RC 3rd, Golde TE, Jankowsky JL (2011 ) Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-beta immunotherapy. J Neurosci 31:4124–4136.

    Not in our library10.1523/jneurosci.5077-10.2011

87. 87.

    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.

    Not in our library10.1016/j.cell.2015.01.049

88. 88.

    Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, Yuan P, Mahan TE, Shi Y, Gilfillan S, Cella M, Grutzendler J, DeMattos RB, Cirrito JR, Holtzman DM, Colonna M (2016 ) TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med 213:667–675.

    Not in our library10.1084/jem.20151948

89. 89.

    Wu TD, Reeder J, Lawrence M, Becker G, Brauer MJ (2016 ) GMAP and GSNAP for genomic sequence alignment: enhancements to speed, accuracy, and functionality. Methods Mol Biol 1418:283–334.

    Not in our library10.1007/978-1-4939-3578-9_15

90. 90.
    Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy · 2019

    Not checked
91. 91.

    Wu W, Glinka A, Delius H, Niehrs C (2000 ) Mutual antagonism between dickkopf1 and dickkopf2 regulates Wnt/beta-catenin signalling. Curr Biol 10:1611–1614.

    Not in our library10.1016/s0960-9822(00)00868-x

92. 92.

    Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M (2016 ) TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91:328–340.

    Not in our library10.1016/j.neuron.2016.06.015

93. 93.

    Yeh FL, Hansen DV, Sheng M (2017 ) TREM2, microglia, and neurodegenerative diseases. Trends Mol Med 23:512–533.

    Not in our library10.1016/j.molmed.2017.03.008

94. 94.

    Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM (2007 ) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351.

    Not in our library10.1016/j.neuron.2007.01.010

95. 95.

    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.

    Not in our library10.1016/j.neuron.2016.09.016

96. 96.

    Zhao Y, Wu X, Li X, Jiang LL, Gui X, Liu Y, Sun Y, Zhu B, Piña-Crespo JC, Zhang M, Zhang N, Chen X, Bu G, An Z, Huang TY, Xu H (2018 ) TREM2 is a receptor for beta-amyloid that mediates microglial function. Neuron 97:1023–1031.e7.

    Not in our library10.1016/j.neuron.2018.01.031

97. 97.

    Zheng H, Jia L, Liu CC, Rong Z, Zhong L, Yang L, Chen XF, Fryer JD, Wang X, Zhang YW, Xu H, Bu G (2017 ) TREM2 promotes microglial survival by activating Wnt/beta-catenin pathway. J Neurosci 37:1772–1784.

    Not in our library10.1523/jneurosci.2459-16.2017

98. 98.

    Zulfiqar S, Tanriöver G (2017 ) β-Catenin pathway is involved in TREM2-mediated microglial survival. J Neurosci 37:7073–7075.

    Not in our library10.1523/jneurosci.1087-17.2017

Cited by papers we hold 9

• A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models · 2023
  No notice
• Microglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials · 2023
  No notice
• Microglial VPS35 deficiency impairs Aβ phagocytosis and Aβ-induced disease-associated microglia, and enhances Aβ associated pathology · 2022
  Not checked
• Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models · 2022
  No notice
• TREM2 dependent and independent functions of microglia in Alzheimer’s disease · 2022
  No notice
• Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine · 2022
  No notice
• Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function · 2021
  No notice
• Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions · 2020
  No notice
• Higher CSF sTREM2 and microglia activation are associated with slower rates of beta‐amyloid accumulation · 2020
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.