CoChat
Sign Up
Cited by 29Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

The NeuroImmune System in Alzheimer's Disease: The Glass is Half Full

Open access
Hickman, Suzanne E., El Khoury, Joseph·2012·Journal of Alzheimer's Disease
DOI 10.3233/jad-2012-129027PMC PMC8176079
Open this paper in CoChat — free account

Abstract

It is well established that microglia, the neuroimmune cells of the brain, are associated with amyloid-β (Aβ) deposits in Alzheimer's disease (AD). However, the roles of these cells and other mononuclear phagocytes such as monocytes and macrophages in AD pathogenesis and progression have been elusive. Clues to mononuclear phagocyte involvement came with the demonstration that Aβ directly activates microglia and monocytes to produce neurotoxins, signifying that a receptor mediated interaction of Aβ with these cells may be critical for neurodegeneration seen in AD. Also, in AD brain, mononuclear phagocyte distribution changes from a uniform pattern that covers the brain parenchyma to distinct clusters intimately associated with areas of Aβ deposition, but the driving force behind this choreography was unclear. Here, we review our recent work identifying mononuclear phagocyte receptors for Aβ and unraveling mechanisms of recruitment of these cells to areas of Aβ deposition. While our findings and those of others have added significantly to our understanding of the role of the neuroimmune system in AD, the glass remains half full (or half empty) and a lot remains to be uncovered.

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 · 10.3233/jad-2012-129027

Cites

2 of 2 references verified0 citation errors · 0 not checkable

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?

  • Progression of Alzheimer's disease is associated with reduced Aβ-clearing pathways resulting in Aβ accumulation.

    “Progression of Alzheimer's disease is associated with reduced Aβ-clearing pathways resulting in Aβ accumulation (4–6).”

    From Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice (2019) · cites this paper as [6]

    In the section on persistent Aβ deposition, the paper reports reduced Aβ-binding receptors and degrading enzymes as AD-like pathology progresses in PS1-APP mice. It proposes that diminished clearance leads to greater Aβ accumulation, but presents that link as a possibility rather than an established result for Alzheimer's disease generally. The supplied passages have no page numbers. (LLM, conf=0.82)

    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.

Cites

Flagged first, then by citations

Research works printed but not linked: 50

  1. [1]Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39, 151– 170. 2089275
  2. [3]Rezaie P, Male D (2002) Mesoglia & microglia–a historical review of the concept of mononuclear phagocytes within the central nervous system. J Hist Neurosci 11, 325– 374. 12557654
  3. [4]Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314– 1318. 15831717
  4. [5]Chan WY, Kohsaka S, Rezaie P (2007) The origin and cell lineage of microglia: New concepts. Brain Res Rev 53, 344– 354. 17188751
  5. [6]Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, Capecchi MR (2010) Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141, 775– 785. 20510925 PMC2894573
  6. [7]Priller J, Prinz M, Heikenwalder M, Zeller N, Schwarz P, Heppner FL, Aguzzi A (2006) Early and rapid engraftment of bone marrow-derived microglia in scrapie. J Neurosci 26, 11753– 11762. 17093096 PMC6674798
  7. [8]Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Bruck W, Priller J, Prinz M (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10, 1544– 1553. 18026096
  8. [9]El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, Freeman MW, Luster AD (2003) CD36 mediates the innate host response to beta-amyloid. J Exp Med 197, 1657– 1666. 12796468 PMC2193948
  9. [10]Webster SD, Park M, Fonseca MI, Tenner AJ (2000) Structural and functional evidence for microglial expression of C1qR(P), the C1q receptor that enhances phagocytosis. J Leukoc Biol 67, 109– 116. 10648005
  10. [11]Ulvestad E, Williams K, Bjerkvig R, Tiekotter K, Antel J, Matre R (1994) Human microglial cells have phenotypic and functional characteristics in common with both macrophages and dendritic antigen-presenting cells. J Leukoc Biol 56, 732– 740. 7996050
  11. [12]Ribes S, Ebert S, Regen T, Agarwal A, Tauber SC, Czesnik D, Spreer A, Bunkowski S, Eiffert H, Hanisch UK, Hammerschmidt S, Nau R (2009) Toll-like receptor stimulation enhances phagocytosis and intracellular killing of nonen-capsulated and encapsulated Streptococcus pneumoniae by murine microglia. Infect Immun 78, 865– 871. 19933834 PMC2812218
  12. [13]Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201, 647– 657. 15728241 PMC2213053
  13. [14]Beauvillain C, Donnou S, Jarry U, Scotet M, Gascan H, Delneste Y, Guermonprez P, Jeannin P, Couez D (2008) Neonatal and adult microglia cross-present exogenous antigens. Glia 56, 69– 77. 17932942
  14. [15]Guillemin GJ, Brew BJ (2004) Microglia, macrophages, perivascular macrophages, and pericytes: A review of function and identification. J Leukoc Biol 75, 388– 397. 14612429
  15. [16]Fabriek BO, Van Haastert ES, Galea I, Polfliet MM, Dopp ED, Van Den Heuvel MM, Van Den Berg TK, De Groot CJ, Van Der Valk P, Dijkstra CD (2005) CD163-positive perivascular macrophages in the human CNS express molecules for antigen recognition and presentation. Glia 51, 297– 305. 15846794
  16. [17]Kim WK, Alvarez X, Fisher J, Bronfin B, Westmoreland S, McLaurin J, Williams K (2006) CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood. Am J Pathol 168, 822– 834. 16507898 PMC1606539
  17. [18]Audoy-Remus J, Richard JF, Soulet D, Zhou H, Kubes P, Vallieres L (2008) Rod-Shaped monocytes patrol the brain vasculature and give rise to perivascular macrophages under the influence of proinflammatory cytokines and angiopoietin-2. J Neurosci 28, 10187– 10199. 18842879 PMC6671016
  18. [19]Bechmann I, Priller J, Kovac A, Bontert M, Wehner T, Klett FF, Bohsung J, Stuschke M, Dirnagl U, Nitsch R (2001) Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages. Eur J Neurosci 14, 1651– 1658. 11860459
  19. [21]Tooyama I, Kimura H, Akiyama H, McGeer PL (1990) Reactive microglia express class I and class II major histocompatibility complex antigens in Alzheimer’s disease. Brain Res 523, 273– 280. 2400911
  20. [22]McGeer EG, McGeer PL (2010) Neuroinflammation in Alzheimer’s disease and mild cognitive impairment: A field in its infancy. J Alzheimers Dis 19, 355– 361. 20061650
  21. [23]Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, Ferrari D, Rossi F (1995) Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374, 647– 650. 7715705
  22. [24]Fraser I, Hughes D, Gordon S (1993) Divalent cation-independent macrophage adhesion inhibited by monoclonal antibody to murine scavenger receptor. Nature 364, 343– 346. 8332192
  23. [25]el Khoury J, Thomas CA, Loike JD, Hickman SE, Cao L, Silverstein SC (1994) Macrophages adhere to glucose-modified basement membrane collagen IV via their scavenger receptors. J Biol Chem 269, 10197– 10200. 8144597
  24. [26]Jiang H, Burdick D, Glabe CG, Cotman CW, Tenner AJ (1994) beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain. J Immunol 152, 5050– 5059. 8176223
  25. [28]El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD (1996) Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382, 716– 719. 8751442
  26. [29]Maxeiner H, Husemann J, Thomas CA, Loike JD, El Khoury J, Silverstein SC (1998) Complementary roles for scavenger receptor A and CD36 of human monocyte-derived macrophages in adhesion to surfaces coated with oxidized low-density lipoproteins and in secretion of H2O2. J Exp Med 188, 2257– 2265. 9858512 PMC2212435
  27. [30]Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, Luster AD, Silverstein SC, El-Khoury JB (2002) CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer’s disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol 160, 101– 112. 11786404 PMC1867121
  28. [31]Means TK, Mylonakis E, Tampakakis E, Colvin RA, Seung E, Puckett L, Tai MF, Stewart CR, Pukkila-Worley R, Hickman SE, Moore KJ, Calderwood SB, Hacohen N, Luster AD, El Khoury J (2009) Evolutionarily conserved recognition and innate immunity to fungal pathogens by the scavenger receptors SCARF1 and CD36. J Exp Med 206, 637– 653. 19237602 PMC2699123
  29. [32]Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11, 155– 161. 20037584 PMC2809046
  30. [33]Wilkinson K, Boyd JD, Glicksman M, Moore KJ, El Khoury J (2011) A high-content drug screen identifies ursolic acid as an inhibitor of amyloid-{beta} interactions with its receptor CD36. J Biol Chem 286(40), 34914– 34922. 21835916 PMC3186388
  31. [34]Djukic M, Mildner A, Schmidt H, Czesnik D, Bruck W, Priller J, Nau R, Prinz M (2006) Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice. Brain 129, 2394– 2403. 16891321
  32. [35]Charlier C, Nielsen K, Daou S, Brigitte M, Chretien F, Dromer F (2009) Evidence of a role for monocytes in dissemination and brain invasion by Cryptococcus neoformans. Infect Immun 77, 120– 127. 18936186 PMC2612285
  33. [36]Chretien F, Lortholary O, Kansau I, Neuville S, Gray F, Dromer F (2002) Pathogenesis of cerebral Cryptococcus neoformans infection after fungemia. J Infect Dis 186, 522– 530. 12195380
  34. [37]El Khoury J (2012) The blood brain barrier and pathogens: Hadrian’s wall or a Dardanian gate? Virulence 3, 157– 158. 22460634
  35. [38]Remington LT, Babcock AA, Zehntner SP, Owens T (2007) Microglial recruitment, activation, and proliferation in response to primary demyelination. Am J Pathol 170, 1713– 1724. 17456776 PMC1854965
  36. [39]Kokovay E, Cunningham LA (2005) Bone marrow-derived microglia contribute to the neuroinflammatory response and express iNOS in the MPTP mouse model of Parkinson’s disease. Neurobiol Dis 19, 471– 478. 16023589
  37. [40]Viola A, Luster AD (2008) Chemokines and their receptors: Drug targets in immunity and inflammation. Annu Rev Pharmacol Toxicol 48, 171– 197. 17883327
  38. [41]Barlic J, Murphy PM (2007) Chemokine regulation of atherosclerosis. J Leukoc Biol 82, 226– 236. 17329566
  39. [42]Izikson L, Klein RS, Charo IF, Weiner HL, Luster AD (2000) Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. J Exp Med 192, 1075– 1080. 11015448 PMC2193310
  40. [43]Ishizuka K, Kimura T, Igata-yi R, Katsuragi S, Takamatsu J, Miyakawa T (1997) Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer’s disease. Psychiatry Clin Neurosci 51, 135– 138. 9225377
  41. [44]Sokolova A, Hill MD, Rahimi F, Warden LA, Halliday GM, Shepherd CE (2009) Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer’s disease. Brain Pathol 19, 392– 398. 18637012 PMC8094842
  42. [45]El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13, 432– 438. 17351623
  43. [46]Hawkes CA, McLaurin J (2009) Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc Natl Acad Sci U S A 106, 1261– 1266. 19164591 PMC2633563
  44. [47]Kumar-Singh S, Pirici D, McGowan E, Serneels S, Ceuterick C, Hardy J, Duff K, Dickson D, Van Broeckhoven C (2005) Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer’s disease are centered on vessel walls. Am J Pathol 167, 527– 543. 16049337 PMC1603563
  45. [48]Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19, 939– 945. 9354339
  46. [49]Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR (2001) Co-expression of multiple transgenes in mouse CNS: A comparison of strategies. Biomol Eng 17, 157– 165. 11337275
  47. [50]Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28, 8354– 8360. 18701698 PMC2597474
  48. [51]Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, Lossinsky AS, Graves MC, Gustavson A, Sayre J, Sofroni E, Suarez T, Chiappelli F, Bernard G (2005) Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer’s disease patients. J Alzheimers Dis 7, 221– 232; discussion 255–262. 16006665
  49. [52]Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Ikezu T (2007) Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol 170, 680– 692. 17255335 PMC1851864
  50. [53]Liao YF, Wang BJ, Cheng HT, Kuo LH, Wolfe MS (2004) Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J Biol Chem 279, 49523– 49532. 15347683

Cited by

Sorted by citations

Related

Authors
Hickman, S. E., & El Khoury, J.
Affiliations
  • Harvard University (US)
  • Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
ORCID
Hickman, Suzanne E.
Venue
Journal of Alzheimer's Disease
Publisher
SAGE Publications
Published
2012-12-27
Volume
33
Issue
s1
Pages
S295-S302
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-2012-129027
PMC
PMC8176079
OpenAlex
W1560184319
Cited by
29
References
2
Citations by year
2023: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 5 · 2015: 3 · 2014: 4 · 2013: 3 · 2012: 3
FWCI
2.09
Type
journal article
Language
en
Open access
Locations
  • Journal of Alzheimer s Disease (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Dana Foundation
  • National Institutes of Health
  • National Institute on Aging (AG032349, R01AG032349)
  • National Institute of Allergy and Infectious Diseases (AI082660, U24AI082660)
  • National Institute of Neurological Disorders and Stroke (NS059005, R01NS059005)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, neuroimmune system
MeSH terms
Alzheimer Disease, Brain, Humans, Immune System, Macrophages, Monocytes, Microglia

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