CoChat
Sign Up
Cited by 50Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

The Complexity of Microglial Interactions With Innate and Adaptive Immune Cells in Alzheimer’s Disease

Open access
Wyatt-Johnson, Season K., Brutkiewicz, Randy R.·2020·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2020.592359PMC PMC7718034
Open this paper in CoChat — free accountOpen PDF

Abstract

In the naïve mouse brain, microglia and astrocytes are the most abundant immune cells; however, there is a complexity of other immune cells present including monocytes, neutrophils, and lymphocytic cells, such as natural killer (NK) cells, T cells, and B cells. In Alzheimer’s disease (AD), there is high inflammation, reactive microglia, and astrocytes, leaky blood–brain barrier, the buildup of amyloid-beta (Aβ) plaques, and neurofibrillary tangles which attract infiltrating peripheral immune cells that are interacting with the resident microglia. Limited studies have analyzed how these infiltrating immune cells contribute to the neuropathology of AD and even fewer have analyzed their interactions with the resident microglia. Understanding the complexity and dynamics of how these immune cells interact in AD will be important for identifying new and novel therapeutic targets. Thus, this review will focus on discussing our current understanding of how macrophages, neutrophils, NK cells, T cells, and B cells, alongside astrocytes, are altered in AD and what this means for the disorder, as well as how these cells are affected relative to the resident microglia.

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 · 10.3389/fnagi.2020.592359

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?

  • Loss of MHC class II molecules increases Aβ plaques.

    “Notably, the loss of MHC class II molecules has been shown to increase Aβ plaques [3, 6].”

    From Control of the temporal development of Alzheimer’s disease pathology by the MR1/MAIT cell axis (2023) · cites this paper as [3]

    In “T Cells and Microglia in AD” (page unavailable), the review reports that Aβ-specific Th1 cells reduced plaque load in 5xFAD mice, but did not change plaque load in 5xFAD mice lacking MHCII. This supports a role for MHCII in that treatment response, not the broader claim that loss of MHC class II itself increases plaques. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • The 5XFAD mouse is a model of early-onset AD.

    “notably, the 5XFAD mouse is a model of early‐onset AD. 35”

    From The MR1/MAIT cell axis enhances dystrophic neurite development in Alzheimer's disease (2025) · cites this paper as [35]

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 50

Research works printed but not linked: 82

  1. Abel A. M. Yang C. Thakar M. S. Malarkannan S. (2018). Natural killer cells: development. maturation, and clinical utilization. Front. Immunol. 9: 1869. 10.3389/fimmu.2018.01869 30150991 PMC6099181 · DOI · Paper page
  2. Balu D. T. Pantazopoulos H. Huang C. C. Y. Muszynski K. Harvey T. L. Uno Y. (2019). Neurotoxic astrocytes express the d-serine synthesizing enzyme, serine racemase, in Alzheimer’s disease. Neurobiol. Dis. 130: 104511. 10.1016/j.nbd.2019.104511 31212068 PMC6689433 · DOI
  3. Bennett M. L. Bennett F. C. Liddelow S. A. Ajami B. Zamanian J. L. Fernhoff N. B. (2016). New tools for studying microglia in the mouse and human CNS. Proc. Natl. Acad. Sci. U.S.A. 113 E1738– E1746. 10.1073/pnas.1525528113 26884166 PMC4812770 · DOI · Paper page
  4. Blair L. J. Frauen H. D. Zhang B. Nordhues B. A. Bijan S. Lin Y. C. (2015). Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy. Acta Neuropathol. Commun. 3: 8. 10.1186/s40478-015-0186-2 25775028 PMC4353464 · DOI · Paper page
  5. Bradburn S. Murgatroyd C. Ray N. (2019). Neuroinflammation in mild cognitive impairment and Alzheimer’s disease: a meta-analysis. Ageing Res. Rev. 50 1– 8. 10.1016/j.arr.2019.01.002 30610927 · DOI
  6. Cao W. Zheng H. (2018). Peripheral immune system in aging and Alzheimer’s disease. Mol. Neurodegener. 13: 51. 10.1186/s13024-018-0284-2 30285785 PMC6169078 · DOI · Paper page
  7. Ceyzeriat K. Zilli T. Millet P. Frisoni G. B. Garibotto V. Tournier B. B. (2020). Learning from the past: a review of clinical trials targeting amyloid. tau and neuroinflammation in Alzheimer’s disease. Curr. Alzheimer Res. 17 112– 125. 10.2174/1567205017666200304085513 32129164 · DOI
  8. Ciccocioppo F. Lanuti P. Pierdomenico L. Simeone P. Bologna G. Ercolino E. (2019). The Characterization of Regulatory T-Cell Profiles in Alzheimer’s Disease and Multiple Sclerosis. Sci. Rep. 9: 8788. PMC6584558 31217537
  9. Cohen R. M. Rezai-Zadeh K. Weitz T. M. Rentsendorj A. Gate D. Spivak I. (2013). A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J. Neurosci. 33 6245– 6256. 10.1523/JNEUROSCI.3672-12.2013 23575824 PMC3720142 · DOI
  10. Dodiya H. B. Frith M. Sidebottom A. Cao Y. Koval J. Chang E. (2020). Synergistic depletion of gut microbial consortia, but not individual antibiotics, reduces amyloidosis in APPPS1-21 Alzheimer’s transgenic mice. Sci. Rep. 10: 8183. 10.1038/s41598-020-64797-5 32424118 PMC7235236 · DOI
  11. Dudal S. Krzywkowski P. Paquette J. Morissette C. Lacombe D. Tremblay P. (2004). Inflammation occurs early during the Abeta deposition process in TgCRND8 mice. Neurobiol. Aging 25 861– 871. 10.1016/j.neurobiolaging.2003.08.008 15212840 · DOI
  12. El Khoury J. Toft M. Hickman S. E. Means T. K. Terada K. Geula C. (2007). Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13 432– 438. 10.1038/nm1555 17351623 · DOI · Paper page
  13. Fakhoury M. (2018). Microglia and Astrocytes in Alzheimer’s Disease: implications for therapy. Curr. Neuropharmacol. 16 508– 518. 10.2174/1570159X15666170720095240 28730967 PMC5997862 · DOI
  14. Frackowiak J. Wisniewski H. M. Wegiel J. Merz G. S. Iqbal K. Wang K. C. (1992). Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol. 84 225– 233. 10.1007/BF00227813 1414275 · DOI · Paper page
  15. Friker L. L. Scheiblich H. Hochheiser I. V. Brinkschulte R. Riedel D. Latz E. (2020). beta-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia. Cell Rep. 374: e3746 10.1016/j.celrep.2020.02.025 PMC8729885 32187546 · DOI · Paper page
  16. Gate D. Saligrama N. Leventhal O. Yang A. C. Unger M. S. Middeldorp J. (2020). Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577 399– 404. 10.1038/s41586-019-1895-7 31915375 PMC7445078 · DOI · Paper page
  17. Gomez-Arboledas A. Davila J. C. Sanchez-Mejias E. Navarro V. Nunez-Diaz C. Sanchez-Varo R. (2018). Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer’s disease. Glia 66 637– 653. 10.1002/glia.23270 29178139 PMC5814816 · DOI · Paper page
  18. Granger M. W. Franko B. Taylor M. W. Messier C. George-Hyslop P. S. Bennett S. A. (2016). A TgCRND8 mouse model of Alzheimer’s disease exhibits sexual dimorphisms in behavioral indices of cognitive reserve. J. Alzheimers Dis. 51 757– 773. 10.3233/JAD-150587 26890738 · DOI
  19. Grootendorst J. Bour A. Vogel E. Kelche C. Sullivan P. M. Dodart J. C. (2005). Human apoE targeted replacement mouse lines: h-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior. Behav. Brain Res. 159 1– 14. 10.1016/j.bbr.2004.09.019 15794991 · DOI · Paper page
  20. Habib N. McCabe C. Medina S. Varshavsky M. Kitsberg D. Dvir-Szternfeld R. (2020). Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23 701– 706. 10.1038/s41593-020-0624-8 32341542 PMC9262034 · DOI · Paper page
  21. Hagen M. Derudder E. (2020). Inflammation and the alteration of B-cell physiology in aging. Gerontology 66 105– 113. 10.1159/000501963 31553969 · DOI · Paper page
  22. Han F. Perrin R. J. Wang Q. Wang Y. Perlmutter J. S. Morris J. C. (2019). Neuroinflammation and myelin status in Alzheimer’s disease, Parkinson’s disease, and normal aging brains: a small sample study. Parkinsons Dis. 2019: 7975407. 10.1155/2019/7975407 31354934 PMC6637678 · DOI
  23. Hemonnot A. L. Hua J. Ulmann L. Hirbec H. (2019). Microglia in Alzheimer disease: well-known targets and new opportunities. Front. Aging Neurosci. 11: 233. 10.3389/fnagi.2019.00233 31543810 PMC6730262 · DOI · Paper page
  24. Hsiao K. Chapman P. Nilsen S. Eckman C. Harigaya Y. Younkin S. (1996). Correlative memory deficits. Abeta elevation, and amyloid plaques in transgenic mice. Science 274 99– 102. 10.1126/science.274.5284.99 8810256 · DOI · Paper page
  25. Jankowsky J. L. Fadale D. J. Anderson J. Xu G. M. Gonzales V. Jenkins N. A. (2004). Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum. Mol. Genet. 13 159– 170. 10.1093/hmg/ddh019 14645205 · DOI · Paper page
  26. Jay T. R. Hirsch A. M. Broihier M. L. Miller C. M. Neilson L. E. Ransohoff R. M. (2017). Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 37 637– 647. 10.1523/JNEUROSCI.2110-16.2016 28100745 PMC5242410 · DOI · Paper page
  27. Jordao M. J. C. Sankowski R. Brendecke S. M. Sagar, Locatelli G. Tai Y. H. (2019). Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363: eaat755. 10.1126/science.aat7554 30679343 · DOI · Paper page
  28. Kamphuis W. Mamber C. Moeton M. Kooijman L. Sluijs J. A. Jansen A. H. (2012). GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS One 7: e42823. 10.1371/journal.pone.0042823 22912745 PMC3418292 · DOI
  29. Keren-Shaul H. Spinrad A. Weiner A. Matcovitch-Natan O. Dvir-Szternfeld R. Ulland T. K. (2017). A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 127: e1217. 10.1016/j.cell.2017.05.018 28602351 · DOI · Paper page
  30. Kingsley B. S. Gaskin F. Fu S. M. (1988). Human antibodies to neurofibrillary tangles and astrocytes in Alzheimer’s disease. J. Neuroimmunol. 19 89– 99. 10.1016/0165-5728(88)90038-0 3260906 · DOI
  31. Lane C. A. Hardy J. Schott J. M. (2018). Alzheimer’s disease. Eur. J. Neurol. 25 59– 70. 10.1111/ene.13439 28872215 · DOI · Paper page
  32. Lazic D. Sagare A. P. Nikolakopoulou A. M. Griffin J. H. Vassar R. Zlokovic B. V. (2019). 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice. J. Exp. Med. 216 279– 293. 10.1084/jem.20181035 30647119 PMC6363429 · DOI
  33. Le Page A. Bourgade K. Lamoureux J. Frost E. Pawelec G. Larbi A. (2015). NK cells are activated in amnestic mild cognitive impairment but not in mild alzheimer’s disease patients. J. Alzheimers Dis. 46 93– 107. 10.3233/JAD-143054 25720398 · DOI
  34. Ma W. T. Gao F. Gu K. Chen D. K. (2019). The role of monocytes and macrophages in autoimmune diseases: a comprehensive review. Front. Immunol. 10: 1140. 10.3389/fimmu.2019.01140 31178867 PMC6543461 · DOI
  35. Marsh S. E. Abud E. M. Lakatos A. Karimzadeh A. Yeung S. T. Davtyan H. (2016). The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proc. Natl. Acad. Sci. U.S.A. 113 E1316– E1325. 10.1073/pnas.1525466113 26884167 PMC4780638 · DOI · Paper page
  36. Matias I. Morgado J. Gomes F. C. A. (2019). Astrocyte heterogeneity: impact to brain aging and disease. Front. Aging Neurosci. 11: 59. 10.3389/fnagi.2019.00059 30941031 PMC6433753 · DOI · Paper page
  37. Mayadas T. N. Cullere X. Lowell C. A. (2014). The multifaceted functions of neutrophils. Annu. Rev. Pathol. 9 181– 218. 10.1146/annurev-pathol-020712-164023 24050624 PMC4277181 · DOI · Paper page
  38. Merlini M. Kirabali T. Kulic L. Nitsch R. M. Ferretti M. T. (2018). Extravascular CD3+ T cells in brains of alzheimer disease patients correlate with Tau but Not with amyloid pathology: an immunohistochemical study. Neurodegener. Dis. 18 49– 56. 10.1159/000486200 29402847 · DOI
  39. Minkeviciene R. Rheims S. Dobszay M. B. Zilberter M. Hartikainen J. Fulop L. (2009). Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J. Neurosci. 29 3453– 3462. 10.1523/JNEUROSCI.5215-08.2009 19295151 PMC6665248 · DOI
  40. Minter M. R. Hinterleitner R. Meisel M. Zhang C. Leone V. Zhang X. (2017). Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1DeltaE9 murine model of Alzheimer’s disease. Sci. Rep. 7: 10411. 10.1038/s41598-017-11047-w 28874832 PMC5585265 · DOI · Paper page
  41. Montagne A. Zhao Z. Zlokovic B. V. (2017). Alzheimer’s disease: a matter of blood-brain barrier dysfunction? J. Exp. Med. 214 3151– 3169. 10.1084/jem.20171406 29061693 PMC5679168 · DOI · Paper page
  42. Mundt S. Greter M. Flugel A. Becher B. (2019). The CNS Immune Landscape from the Viewpoint of a T Cell. Trends Neurosci. 42 667– 679. 10.1016/j.tins.2019.07.008 31474310 · DOI
  43. Myers A. McGonigle P. (2019). Overview of Transgenic Mouse Models for Alzheimer’s Disease. Curr. Protoc. Neurosci. 89: e81. 10.1002/cpns.81 31532917 · DOI
  44. Nation D. A. Sweeney M. D. Montagne A. Sagare A. P. D’Orazio L. M. Pachicano M. (2019). Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 25 270– 276. 10.1038/s41591-018-0297-y 30643288 PMC6367058 · DOI · Paper page
  45. Neurath M. F. Kaplan M. H. (2017). Th9 cells in immunity and immunopathological diseases. Semin. Immunopathol. 39 1– 4. 10.1007/s00281-016-0611-z 27900451 · DOI
  46. Nikolajczyk B. S. (2010). B cells as under-appreciated mediators of non-auto-immune inflammatory disease. Cytokine 50 234– 242. 10.1016/j.cyto.2010.02.022 20382544 PMC2917985 · DOI
  47. Nordengen K. Kirsebom B. E. Henjum K. Selnes P. Gisladottir B. Wettergreen M. (2019). Glial activation and inflammation along the Alzheimer’s disease continuum. J. Neuroinflamm. 16: 46. 10.1186/s12974-019-1399-2 30791945 PMC6383268 · DOI · Paper page
  48. Ofengeim D. Mazzitelli S. Ito Y. DeWitt J. P. Mifflin L. Zou C. (2017). RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 114 E8788– E8797. 10.1073/pnas.1714175114 28904096 PMC5642727 · DOI · Paper page
  49. Park J. Baik S. H. Mook-Jung I. Irimia D. Cho H. (2019). Mimicry of central-peripheral immunity in Alzheimer’s disease and discovery of neurodegenerative roles in neutrophil. Front. Immunol. 10: 2231. 10.3389/fimmu.2019.02231 31611872 PMC6776120 · DOI
  50. Prinz M. Priller J. (2017). The role of peripheral immune cells in the CNS in steady state and disease. Nat. Neurosci. 20 136– 144. 10.1038/nn.4475 28092660 · DOI · Paper page
  51. Radde R. Bolmont T. Kaeser S. A. Coomaraswamy J. Lindau D. Stoltze L. (2006). Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 7 940– 946. 10.1038/sj.embor.7400784 16906128 PMC1559665 · DOI · Paper page
  52. Rajan W. D. Wojtas B. Gielniewski B. Miro-Mur F. Pedragosa J. Zawadzka M. (2020). Defining molecular identity and fates of CNS-border associated macrophages after ischemic stroke in rodents and humans. Neurobiol. Dis. 137: 104722. 10.1016/j.nbd.2019.104722 31926295 · DOI
  53. Ratliff M. Alter S. McAvoy K. Frasca D. Wright J. A. Zinkel S. S. (2015). In aged mice, low surrogate light chain promotes pro-B-cell apoptotic resistance, compromises the PreBCR checkpoint, and favors generation of autoreactive, phosphorylcholine-specific B cells. Aging Cell 14 382– 390. 10.1111/acel.12302 25727904 PMC4406667 · DOI
  54. Rezai-Zadeh K. Gate D. Town T. (2009). CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J. Neuroimmune Pharmacol. 4 462– 475. 10.1007/s11481-009-9166-2 19669892 PMC2773117 · DOI
  55. Rostami J. Fotaki G. Sirois J. Mzezewa R. Bergstrom J. Essand M. (2020). Astrocytes have the capacity to act as antigen-presenting cells in the Parkinson’s disease brain. J. Neuroinflamm. 17: 119. 10.1186/s12974-020-01776-7 32299492 PMC7164247 · DOI · Paper page
  56. Schetters S. T. T. Gomez-Nicola D. Garcia-Vallejo J. J. Van Kooyk Y. (2017). Neuroinflammation: microglia and T Cells Get Ready to Tango. Front. Immunol. 8: 1905. 10.3389/fimmu.2017.01905 29422891 PMC5788906 · DOI
  57. Scholtzova H. Kascsak R. J. Bates K. A. Boutajangout A. Kerr D. J. Meeker H. C. (2009). Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer’s disease-related pathology. J. Neurosci. 29 1846– 1854. 10.1523/JNEUROSCI.5715-08.2009 19211891 PMC2699573 · DOI · Paper page
  58. Shi Y. Holtzman D. M. (2018). Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat. Rev. Immunol. 18 759– 772. 10.1038/s41577-018-0051-1 30140051 PMC6425488 · DOI · Paper page
  59. Solana C. Tarazona R. Solana R. (2018). Immunosenescence of natural killer cells, inflammation, and Alzheimer’s disease. Int. J. Alzheimers Dis. 2018: 3128758. 10.1155/2018/3128758 30515321 PMC6236558 · DOI
  60. Srinivasan K. Friedman B. A. Larson J. L. Lauffer B. E. Goldstein L. D. Appling L. L. (2016). Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses. Nat. Commun. 7: 11295. 10.1038/ncomms11295 27097852 PMC4844685 · DOI · Paper page
  61. Sudduth T. L. Greenstein A. Wilcock D. M. (2013). Intracranial injection of Gammagard, a human IVIg, modulates the inflammatory response of the brain and lowers Abeta in APP/PS1 mice along a different time course than anti-Abeta antibodies. J. Neurosci. 33 9684– 9692. 10.1523/JNEUROSCI.1220-13.2013 23739965 PMC3839584 · DOI
  62. Tai L. M. Youmans K. L. Jungbauer L. Yu C. Ladu M. J. (2011). Introducing human APOE into abeta transgenic mouse models. Int. J. Alzheimers Dis. 2011: 810981. 10.4061/2011/810981 22028984 PMC3199079 · DOI · Paper page
  63. Tarlinton D. (2019). B cells still front and centre in immunology. Nat. Rev. Immunol. 19 85– 86. 10.1038/s41577-018-0107-2 30602730 · DOI
  64. Tecchio C. Micheletti A. Cassatella M. A. (2014). Neutrophil-derived cytokines: facts beyond expression. Front. Immunol. 5: 508. 10.3389/fimmu.2014.00508 25374568 PMC4204637 · DOI · Paper page
  65. Thanopoulou K. Fragkouli A. Stylianopoulou F. Georgopoulos S. (2010). Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc. Natl. Acad. Sci. U.S.A. 107 20816– 20821. 10.1073/pnas.1005888107 21076037 PMC2996412 · DOI · Paper page
  66. Unger M. S. Schernthaner P. Marschallinger J. Mrowetz H. Aigner L. (2018). Microglia prevent peripheral immune cell invasion and promote an anti-inflammatory environment in the brain of APP-PS1 transgenic mice. J. Neuroinflamm. 15: 274. 10.1186/s12974-018-1304-4 30241479 PMC6151006 · DOI
  67. Vainchtein I. D. Molofsky A. V. (2020). Astrocytes and Microglia: in sickness and in health. Trends Neurosci. 43 144– 154. 10.1016/j.tins.2020.01.003 32044129 PMC7472912 · DOI · Paper page
  68. van de Haar H. J. Burgmans S. Jansen J. F. van Osch M. J. van Buchem M. A. Muller M. (2016). Blood-brain barrier leakage in patients with early Alzheimer disease. Radiology 281 527– 535. 10.1148/radiol.2016152244 27243267 · DOI · Paper page
  69. Vida C. Martinez de Toda I. Garrido A. Carro E. Molina J. A. De la Fuente M. (2017). Impairment of Several Immune Functions and Redox State in Blood Cells of Alzheimer’s Disease Patients. Relevant Role of Neutrophils in Oxidative Stress. Front. Immunol. 8: 1974. 10.3389/fimmu.2017.01974 29375582 PMC5768621 · DOI
  70. Villacampa N. Heneka M. T. (2018). Microglia: you’ll never walk alone! Immunity 48 195– 197. 10.1016/j.immuni.2018.02.009 29466750 · DOI
  71. Wang J. (2018). Neutrophils in tissue injury and repair. Cell Tissue Res. 371 531– 539. 10.1007/s00441-017-2785-7 29383445 PMC5820392 · DOI
  72. Webers A. Heneka M. T. Gleeson P. A. (2020). The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer’s disease. Immunol. Cell Biol. 98 28– 41. 10.1111/imcb.12301 31654430 · DOI
  73. Williams P. D. Zlokovic B. V. Griffin J. H. Pryor K. E. Davis T. P. (2012). Preclinical safety and pharmacokinetic profile of 3K3A-APC, a novel, modified activated protein C for ischemic stroke. Curr. Pharm. Des. 18 4215– 4222. 10.2174/138161212802430413 22632606 PMC3472038 · DOI
  74. Wisniewski H. M. Barcikowska M. Kida E. (1991). Phagocytosis of beta/A4 amyloid fibrils of the neuritic neocortical plaques. Acta Neuropathol. 81 588– 590. 10.1007/BF00310142 1858487 · DOI
  75. Wyatt-Johnson S. K. Brewster A. L. (2020). Emerging Roles for Microglial Phagocytic Signaling in Epilepsy. Epilepsy Curr. 20 33– 38. 10.1177/1535759719890336 31791133 PMC7020537 · DOI
  76. Xu S. Gaskin F. (1997). Increased incidence of anti-beta-amyloid autoantibodies secreted by Epstein-Barr virus transformed B cell lines from patients with Alzheimer’s disease. Mech. Ageing Dev. 94 213– 222. 10.1016/s0047-6374(96)01861-1 9147373 · DOI
  77. Yue M. Hanna A. Wilson J. Roder H. Janus C. (2011). Sex difference in pathology and memory decline in rTg4510 mouse model of tauopathy. Neurobiol. Aging 32 590– 603. 10.1016/j.neurobiolaging.2009.04.006 19427061 · DOI
  78. Zenaro E. Pietronigro E. Della Bianca V. Piacentino G. Marongiu L. Budui S. (2015). Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat. Med. 21 880– 886. 10.1038/nm.3913 26214837 · DOI · Paper page
  79. Zhang L. Xu J. Gao J. Chen P. Yin M. Zhao W. (2019). Decreased immunoglobulin G in brain regions of elder female APOE4-TR mice accompany with Abeta accumulation. Immun. Ageing 16: 2. 10.1186/s12979-018-0142-7 30700991 PMC6347753 · DOI
  80. Zhang Y. Sloan S. A. Clarke L. E. Caneda C. Plaza C. A. Blumenthal P. D. (2016). Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse. Neuron 89 37– 53. 10.1016/j.neuron.2015.11.013 26687838 PMC4707064 · DOI · Paper page
  81. Zhou Y. Ulland T. K. Colonna M. (2018). TREM2-dependent effects on microglia in Alzheimer’s disease. Front. Aging Neurosci. 10: 202. 10.3389/fnagi.2018.00202 30038567 PMC6046445 · DOI
  82. Zilka N. Kazmerova Z. Jadhav S. Neradil P. Madari A. Obetkova D. (2012). Who fans the flames of Alzheimer’s disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways. J. Neuroinflamm. 9: 47. 10.1186/1742-2094-9-47 22397366 PMC3334709 · DOI

Authors
Wyatt-Johnson, S. K., & Brutkiewicz, R. R.
Affiliations
Indiana University Indianapolis (US)
Corresponding author
Brutkiewicz, Randy R.
ORCID
Brutkiewicz, Randy R.
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2020-11-19
Volume
12
Pages
592359-592359
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2020.592359
PMC
PMC7718034
OpenAlex
W3099193954
Cited by
50
References
110
Citations by year
2026: 3 · 2025: 8 · 2024: 14 · 2023: 8 · 2022: 10 · 2021: 7
FWCI
0.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by)
Funders
School of Medicine, Indiana University
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, microglia, innate immunity, adaptive immunity, astrocytes, monocytes, neutrophils, natural killer cells, T cells, B cells, peripheral immune cell infiltration, neuroinflammation, reactive microglia, amyloid plaques, blood-brain barrier disruption, neurofibrillary tangles, immune cell interactions

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