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Cited by 37Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

The dense-core plaques of Alzheimer’s disease are granulomas

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Lemke, Greg, Huang, Youtong·2022·Journal of Experimental Medicine
DOI 10.1084/jem.20212477PMC PMC9225945
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Abstract

Dense-core plaques, whose centers contain highly polymerized and compacted aggregates of amyloid β peptides, are one of the two defining histopathological features of Alzheimer’s disease. Recent findings indicate that these plaques do not form spontaneously but are instead constructed by microglia, the tissue macrophages of the central nervous system. We discuss cellular, structural, functional, and gene expression criteria by which the microglial assembly of dense-core plaques in the Alzheimer’s brain parallels the construction of granulomas by macrophages in other settings. We compare the genesis of these plaques to the macrophage assembly of mycobacterial granulomas, the defining histopathological features of tuberculosis. We suggest that if dense-core plaques are indeed granulomas, their simple disassembly may be contraindicated as an Alzheimer’s therapy.

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  • Filamentous plaques are neurotoxic whereas compact dense-core plaques are relatively benign.

    “Interestingly, it was previously reported that filamentous plaques are neurotoxic whereas compact dense-core plaques are relatively benign [38, 52].”

    From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [52]

    The Introduction says Aβ oligomers and proto-fibrils that form diffuse plaques are mostly neurotoxic in vitro; it does not call those plaques “filamentous.” In “Implications of the granuloma hypothesis,” the authors suggest dense-core plaques may be less damaging than dispersed oligomers and proto-fibrils, but explicitly say the plaques are not beneficial. The claim turns that qualified comparison into a categorical statement that dense-core plaques are relatively benign. (LLM, conf=0.88)

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References 125 · Cited by 37

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  1. Adams, 1976, The granulomatous inflammatory response. A review, Am. J. Pathol., 84, 164
  2. Alzheimer, 1995, An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”, Clin. Anat., 8, 429, 10.1002/ca.980080612 · DOI · Paper page
  3. Annunziata, 2013, Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-beta secretion via deregulated lysosomal exocytosis, Nat. Commun., 4, 2734, 10.1038/ncomms3734 · DOI · Paper page
  4. Arbo, 2020, Endosomal dysfunction impacts extracellular vesicle release: Central role in Aβ pathology, Ageing Res. Rev., 58, 101006, 10.1016/j.arr.2019.101006 · DOI
  5. Baghallab, 2018, Epitomic characterization of the specificity of the anti-amyloid Aβ monoclonal antibodies 6E10 and 4G8, J. Alzheim. Dis., 66, 1235, 10.3233/JAD-180582 · DOI · Paper page
  6. Beck, 1995, The thymidine kinase/ganciclovir-mediated “suicide” effect is variable in different tumor cells, Hum. Gene Ther., 6, 1525, 10.1089/hum.1995.6.12-1525 · DOI
  7. Cadena, 2017, Heterogeneity in tuberculosis, Nat. Rev. Immunol., 17, 691, 10.1038/nri.2017.69 · DOI
  8. Cambier, 2014, Host evasion and exploitation schemes of Mycobacterium tuberculosis, Cell, 159, 1497, 10.1016/j.cell.2014.11.024 · DOI
  9. Choi, 2009, Preclinical properties of 18F-AV-45: A PET agent for Abeta plaques in the brain, J. Nucl. Med., 50, 1887, 10.2967/jnumed.109.065284 · DOI
  10. Choi, 2012, Correlation of amyloid PET ligand florbetapir F 18 binding with Aβ aggregation and neuritic plaque deposition in postmortem brain tissue, Alzheimer Dis. Assoc. Disord., 26, 8, 10.1097/WAD.0b013e31821300bc · DOI
  11. Cohen, 2018, Alveolar macrophages provide an early Mycobacterium tuberculosis niche and initiate dissemination, Cell Host Microbe, 24, 439, 10.1016/j.chom.2018.08.001 · DOI
  12. Condello, 2015, Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques, Nat. Commun., 6, 6176, 10.1038/ncomms7176 · DOI · Paper page
  13. Cooper, 2009, Cell-mediated immune responses in tuberculosis, Annu. Rev. Immunol., 27, 393, 10.1146/annurev.immunol.021908.132703 · DOI
  14. Coric, 2015, Targeting prodromal Alzheimer disease with avagacestat: A randomized clinical trial, JAMA Neurol., 72, 1324, 10.1001/jamaneurol.2015.0607 · DOI · Paper page
  15. Cronan, 2021, A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization, Cell, 184, 1757, 10.1016/j.cell.2021.02.046 · DOI
  16. Dagher, 2015, Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice, J. Neuroinflammation, 12, 139, 10.1186/s12974-015-0366-9 · DOI · Paper page
  17. Das, 2019, A close look at BACE1 inhibitors for Alzheimer’s disease treatment, CNS Drugs, 33, 251, 10.1007/s40263-019-00613-7 · DOI
  18. Davis, 2009, The role of the granuloma in expansion and dissemination of early tuberculous infection, Cell, 136, 37, 10.1016/j.cell.2008.11.014 · DOI
  19. Di Paolo, 2011, Linking lipids to Alzheimer’s disease: Cholesterol and beyond, Nat. Rev. Neurosci., 12, 284, 10.1038/nrn3012 · DOI · Paper page
  20. Filocamo, 2011, Lysosomal storage disorders: Molecular basis and laboratory testing, Hum. Genom., 5, 156, 10.1186/1479-7364-5-3-156 · DOI
  21. Flynn, 1992, Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection, Proc. Natl. Acad. Sci. USA, 89, 12013, 10.1073/pnas.89.24.12013 · DOI
  22. Fu, 2012, Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia., Glia, 60, 993, 10.1002/glia.22331 · DOI · Paper page
  23. Gao, 2018, Genetic variation within endolysosomal system is associated with late-onset Alzheimer’s disease, Brain, 141, 2711, 10.1093/brain/awy197 · DOI
  24. Gideon, 2022, Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control, Immunity, 55, 827, 10.1016/j.immuni.2022.04.004 · DOI
  25. Glenner, 1984, The amyloid deposits in Alzheimer’s disease: Their nature and pathogenesis, Appl. Pathol., 2, 357
  26. Gonzalez, 2014, T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases, J. Neuroinflammation, 11, 201, 10.1186/s12974-014-0201-8 · DOI
  27. Huang, 2018, Growth of Mycobacterium tuberculosis in vivo segregates with host macrophage metabolism and ontogeny, J. Exp. Med., 215, 1135, 10.1084/jem.20172020 · DOI
  28. Jaffe, 2021, US FDA defends approval of Alzheimer’s disease drug, Lancet, 398, 12, 10.1016/S0140-6736(21)01455-0 · DOI
  29. Jagust, 2016, Is amyloid-beta harmful to the brain? Insights from human imaging studies, Brain, 139, 23, 10.1093/brain/awv326 · DOI · Paper page
  30. Jansen, 2019, Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk, Nat. Genet., 51, 404, 10.1038/s41588-018-0311-9 · DOI · Paper page
  31. Johnson, 2009, Macrophage heterogeneity in atherosclerotic plaques, Curr. Opin. Lipidol., 20, 370, 10.1097/MOL.0b013e3283309848 · DOI · Paper page
  32. Keilani, 2012, Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-beta peptide, J. Neurosci., 32, 5223, 10.1523/JNEUROSCI.4860-11.2012 · DOI
  33. Kepe, 2013, Amyloid-beta positron emission tomography imaging probes: A critical review, J. Alzheim. Dis., 36, 613, 10.3233/JAD-130485 · DOI
  34. Keren-Shaul, 2017, A unique microglia type associated with restricting development of Alzheimer’s disease, Cell, 169, 1276, 10.1016/j.cell.2017.05.018 · DOI · Paper page
  35. Klunk, 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, 10.1093/jnen/61.9.797 · DOI · Paper page
  36. Klunk, 2004, Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B, Ann. Neurol., 55, 306, 10.1002/ana.20009 · DOI · Paper page
  37. Lambert, 2013, Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease, Nat. Genet., 45, 1452, 10.1038/ng.2802 · DOI · Paper page
  38. Lee, 2002, Amyloid binding ligands as Alzheimer’s disease therapies, Neurobiol. Aging, 23, 1039, 10.1016/s0197-4580(02)00121-5 · DOI
  39. Lemke, 2019, How macrophages deal with death, Nat. Rev. Immunol., 19, 539, 10.1038/s41577-019-0167-y · DOI
  40. Li, 2018, Microglia and macrophages in brain homeostasis and disease, Nat. Rev. Immunol., 18, 225, 10.1038/nri.2017.125 · DOI · Paper page
  41. Liegeois, 2018, The interstitial macrophage: A long-neglected piece in the puzzle of lung immunity, Cell Immunol., 330, 91, 10.1016/j.cellimm.2018.02.001 · DOI
  42. Marsh, 2016, The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function, Proc. Natl. Acad. Sci. USA, 113, E1316, 10.1073/pnas.1525466113 · DOI · Paper page
  43. Masters, 1985, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proc. Natl. Acad. Sci. USA, 82, 4245, 10.1073/pnas.82.12.4245 · DOI · Paper page
  44. Masuda, 2020, Novel Hexb-based tools for studying microglia in the CNS, Nat. Immunol., 21, 802, 10.1038/s41590-020-0707-4 · DOI · Paper page
  45. Mathys, 2019, Single-cell transcriptomic analysis of Alzheimer’s disease, Nature, 570, 332, 10.1038/s41586-019-1195-2 · DOI · Paper page
  46. Molina-Ruiz, 2015, Foreign body granulomas, Dermatol. Clin., 33, 497, 10.1016/j.det.2015.03.014 · DOI
  47. Morabito, 2021, Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer’s disease, Nat. Genet., 53, 1143, 10.1038/s41588-021-00894-z · DOI · Paper page
  48. Mori, 2001, Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice, J. Neuropathol. Exp. Neurol., 60, 778, 10.1093/jnen/60.8.778 · DOI
  49. Mullard, 2021, FDA approval for Biogen’s aducanumab sparks Alzheimer disease firestorm, Nat. Rev. Drug Discov., 20, 496, 10.1038/d41573-021-00099-3 · DOI
  50. Myers, 2019, Overview of transgenic mouse models for Alzheimer’s disease, Curr. Protoc. Neurosci., 89, 10.1002/cpns.81 · DOI
  51. Nimmerjahn, 2005, Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo, Science, 308, 1314, 10.1126/science.1110647 · DOI · Paper page
  52. O’Brien, 2011, Amyloid precursor protein processing and Alzheimer’s disease, Annu. Rev. Neurosci., 34, 185, 10.1146/annurev-neuro-061010-113613 · DOI · Paper page
  53. O’Dowd, 1986, Molecular heterogeneity in the infantile and juvenile forms of Sandhoff disease (O-variant GM2 gangliosidosis), J. Biol. Chem., 261, 12680, 10.1016/s0021-9258(18)67145-5 · DOI
  54. O’Dowd, 1985, Isolation of cDNA clones coding for the beta subunit of human beta-hexosaminidase, Proc. Natl. Acad. Sci. USA, 82, 1184, 10.1073/pnas.82.4.1184 · DOI
  55. Otero, 2009, Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin, Nat. Immunol., 10, 734, 10.1038/ni.1744 · DOI · Paper page
  56. Paasila, 2019, The relationship between the morphological subtypes of microglia and Alzheimer’s disease neuropathology, Brain Pathol., 29, 726, 10.1111/bpa.12717 · DOI
  57. Pagan, 2014, Immunity and immunopathology in the tuberculous granuloma, Cold Spring Harb. Perspect. Med., 5, a018499, 10.1101/cshperspect.a018499 · DOI
  58. Pagan, 2018, The Formation and function of granulomas, Annu. Rev. Immunol., 36, 639, 10.1146/annurev-immunol-032712-100022 · DOI
  59. Pike, 1993, Neurodegeneration induced by beta-amyloid peptides in vitro: The role of peptide assembly state, J. Neurosci., 13, 1676, 10.1523/jneurosci.13-04-01676.1993 · DOI · Paper page
  60. Platt, 2012, The cell biology of disease: Lysosomal storage disorders: The cellular impact of lysosomal dysfunction, J. Cell Biol., 199, 723, 10.1083/jcb.201208152 · DOI · Paper page
  61. Prinz, 2021, Microglia and central nervous system-associated macrophages-from origin to disease modulation, Annu. Rev. Immunol., 39, 251, 10.1146/annurev-immunol-093019-110159 · DOI · Paper page
  62. Rabinovici, 2021, Controversy and progress in alzheimer's disease: FDA approval of aducanumab, N. Engl. J. Med., 385, 771, 10.1056/NEJMp2111320 · DOI · Paper page
  63. Ramakrishnan, 2012, Revisiting the role of the granuloma in tuberculosis, Nat. Rev. Immunol., 12, 352, 10.1038/nri3211 · DOI
  64. Ramakrishnan, 2020, Mycobacterium tuberculosis pathogenicity viewed through the lens of molecular Koch’s postulates, Curr. Opin. Microbiol., 54, 103, 10.1016/j.mib.2020.01.011 · DOI
  65. Rodriguez, 2009, Astroglia in dementia and Alzheimer’s disease, Cell Death Differ., 16, 378, 10.1038/cdd.2008.172 · DOI
  66. Roy, 2020, Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease, J. Clin. Invest., 130, 1912, 10.1172/JCI133737 · DOI · Paper page
  67. Russell, 2009, Foamy macrophages and the progression of the human tuberculosis granuloma, Nat. Immunol., 10, 943, 10.1038/ni.1781 · DOI
  68. Rynearson, 2021, Preclinical validation of a potent gamma-secretase modulator for Alzheimer’s disease prevention, J. Exp. Med., 218, 10.1084/jem.20202560 · DOI · Paper page
  69. Sakono, 2010, Amyloid oligomers: formation and toxicity of abeta oligomers, FEBS J., 277, 1348, 10.1111/j.1742-4658.2010.07568.x · DOI
  70. Selkoe, 2001, Alzheimer’s disease: Genes, proteins, and therapy, Physiol. Rev., 81, 741, 10.1152/physrev.2001.81.2.741 · DOI · Paper page
  71. Selkoe, 2016, The amyloid hypothesis of Alzheimer’s disease at 25 years, EMBO Mol. Med., 8, 595, 10.15252/emmm.201606210 · DOI · Paper page
  72. Serrano-Pozo, 2011, Neuropathological alterations in Alzheimer disease, Cold Spring Harb. Perspect. Med., 1, a006189, 10.1101/cshperspect.a006189 · DOI · Paper page
  73. Sevigny, 2016, The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease, Nature, 537, 50, 10.1038/nature19323 · DOI · Paper page
  74. Sharoar, 2019, Sequential formation of different layers of dystrophic neurites in Alzheimer’s brains, Mol. Psychiatr., 24, 1369, 10.1038/s41380-019-0396-2 · DOI · Paper page
  75. Shi, 2017, RTN1 and RTN3 protein are differentially associated with senile plaques in Alzheimer’s brains, Sci. Rep., 7, 6145, 10.1038/s41598-017-05504-9 · DOI
  76. Shim, 2020, Corrigendum: Mycobacterium tuberculosis infection-driven foamy macrophages and their implications in tuberculosis control as targets for host-directed therapy, Front. Immunol., 11, 1601, 10.3389/fimmu.2020.01601 · DOI
  77. Su, 2001, Acidic pH promotes the formation of toxic fibrils from beta-amyloid peptide, Brain Res., 893, 287, 10.1016/s0006-8993(00)03322-9 · DOI · Paper page
  78. Takaki, 2021, Schistosoma mansoni Eggs modulate the timing of granuloma formation to promote transmission, Cell Host Microbe, 29, 58, 10.1016/j.chom.2020.10.002 · DOI
  79. Tao, 2020, siRNA nanoparticles targeting CaMKIIγ in lesional macrophages improve atherosclerotic plaque stability in mice, Sci. Transl. Med., 12, 10.1126/scitranslmed.aay1063 · DOI
  80. Thal, 2015, Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease, Acta Neuropathol., 129, 167, 10.1007/s00401-014-1375-y · DOI · Paper page
  81. Tseng, 1999, Deposition of monomeric, not oligomeric, Abeta mediates growth of Alzheimer’s disease amyloid plaques in human brain preparations, Biochemistry, 38, 10424, 10.1021/bi990718v · DOI
  82. Vergne, 2004, Cell biology of mycobacterium tuberculosis phagosome, Annu. Rev. Cell Dev. Biol., 20, 367, 10.1146/annurev.cellbio.20.010403.114015 · DOI
  83. Wang, 2015, TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model, Cell, 160, 1061, 10.1016/j.cell.2015.01.049 · DOI · Paper page
  84. Whyte, 2022, Lysosomal gene Hexb displays haploinsufficiency in a knock-in mouse model of Alzheimer’s disease, IBRO Neurosci. Rep., 12, 131, 10.1016/j.ibneur.2022.01.004 · DOI
  85. Williams, 1983, Granulomatous inflammation: A review, J. Clin. Pathol., 36, 723, 10.1136/jcp.36.7.723 · DOI
  86. Wyatt-Johnson, 2020, The complexity of microglial interactions with innate and adaptive immune cells in Alzheimer’s disease, Front. Aging Neurosci., 12, 592359, 10.3389/fnagi.2020.592359 · DOI · Paper page
  87. Yin, 2017, Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer’s disease, Neurobiol. Aging, 55, 115, 10.1016/j.neurobiolaging.2017.03.021 · DOI · Paper page
  88. Yuan, 2016, TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy, Neuron, 92, 252, 10.1016/j.neuron.2016.09.016 · DOI · Paper page
  89. Zeng, 2013, Fluorine-18 radiolabeled heterocycles as PET tracers for imaging beta-amyloid plaques in Alzheimer’s disease, Curr. Top. Med. Chem., 13, 909, 10.2174/1568026611313080004 · DOI
  90. Zhou, 2020, Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease, Nat. Med., 26, 131, 10.1038/s41591-019-0695-9 · DOI · Paper page

Authors
Lemke, G., & Huang, Y.
Affiliations
Salk Institute for Biological Studies (US)
Corresponding author
Lemke, Greg
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2022-06-22
Volume
219
Issue
8
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20212477
PMC
PMC9225945
OpenAlex
W4283328375
Cited by
37
References
125
Citations by year
2026: 8 · 2025: 4 · 2024: 12 · 2023: 11 · 2022: 2
FWCI
4.49
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (RF1 AG060748)
  • Coins for Alzheimer’s Research Trust
  • Ferring Pharmaceuticals
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, granuloma, microglia, amyloid-beta, macrophages, tuberculosis, gene expression, neuroinflammation
MeSH terms
Alzheimer Disease, Granuloma, Humans, Amyloid beta-Peptides, Microglia, Plaque, Amyloid

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