The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index.
Macrophages in Alzheimer’s disease: the blood-borne identity
Open accessAbstract
Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder clinically characterized by cognitive decline involving loss of memory, reasoning and linguistic ability. The amyloid cascade hypothesis holds that mismetabolism and aggregation of neurotoxic amyloid-beta (Abeta) peptides, which are deposited as amyloid plaques, are the central etiological events in AD. Recent evidence from AD mouse models suggests that blood-borne mononuclear phagocytes are capable of infiltrating the brain and restricting beta-amyloid plaques, thereby limiting disease progression. These observations raise at least three key questions: (1) what is the cell of origin for macrophages in the AD brain, (2) do blood-borne macrophages impact the pathophysiology of AD and (3) could these enigmatic cells be therapeutically targeted to curb cerebral amyloidosis and thereby slow disease progression? This review begins with a historical perspective of peripheral mononuclear phagocytes in AD, and moves on to critically consider the controversy surrounding their identity as distinct from brain-resident microglia and their potential impact on AD pathology.
Overview
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.
Integrity signals
Registry
Cites
Statistics
Verification
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.
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?
The cited source says what the claim attributes to it.
In the citing paper
“Furthermore, peripheral macrophages may not just be bystanders in the progression of AD, as it has been shown that they are not only more efficient phagocytes of Aβ than microglia, but they are also capable of traversing the blood-brain barrier during times of injury and disease [17–21].”
From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [17]
The cited source says what the claim attributes to it.
In the citing paper
“Furthermore, peripheral macrophages may not just be bystanders in the progression of AD, as it has been shown that they are not only more efficient phagocytes of Aβ than microglia, but they are also capable of traversing the blood-brain barrier during times of injury and disease [17–21].”
From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [17]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Alzheimer's Disease: Genes, Proteins, and Therapy
Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063
Blood Monocytes Consist of Two Principal Subsets with Distinct Migratory Properties
Geissmann, F., Jung, S., & Littman, D. R. (2003) · Immunity · doi:10.1016/s1074-7613(03)00174-2 · Cited by 3,504
Amyloid deposition as the central event in the aetiology of Alzheimer’s disease
Hardy, J., & Allsop, D. (1991) · Trends in Pharmacological Sciences · doi:10.1016/0165-6147(91)90609-v · Cited by 2,538
Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective
Tanzi, R. E., & Bertram, L. (2005) · Cell · doi:10.1016/j.cell.2005.02.008 · Cited by 1,849
Turning Blood into Brain: Cells Bearing Neuronal Antigens Generated in Vivo from Bone Marrow
Mezey, É., Chandross, K. J., Harta, G., Maki, R. A., & McKercher, S. R. (2000) · Science · doi:10.1126/science.290.5497.1779 · Cited by 1,814
From Marrow to Brain: Expression of Neuronal Phenotypes in Adult Mice
Brazelton, T. R., Rossi, F. M. V., Keshet, G. I., & Blau, H. M. (2000) · Science · doi:10.1126/science.290.5497.1775 · Cited by 1,666
Local self-renewal can sustain CNS microglia maintenance and function throughout adult life
Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W., & Rossi, F. M. V. (2007) · Nature Neuroscience · doi:10.1038/nn2014 · Cited by 1,643
Holmes, C., Boche, D., Wilkinson, D., Yadegarfar, G., Hopkins, V., Bayer, A., Jones, R. W., Bullock, R., Love, S., Neal, J. W., et al. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61075-2 · Cited by 1,416 · cited 3×
“Importantly, CAA severity correlates with degree of dementia in humans (Attems et al. 2005), although there has been much debate about whether CAA is a driving force in the pathobiology of AD. Yet, CAA may represent an important therapeutic target in AD. Recently, Hawkes and McLaurin showed that a perivascular subset…”
Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report
Nicoll, J. A. R., Wilkinson, D., Holmes, C., Steart, P., Markham, H., & Weller, R. O. (2003) · Nature Medicine · doi:10.1038/nm840 · Cited by 1,397
Wyss-Coray (2006) · doi:10.1038/nm1484 · Cited by 1,284
Simard, A. R., Soulet, D., Gowing, G., Julien, J.-P., & Rivest, S. (2006) · Neuron · doi:10.1016/j.neuron.2006.01.022 · Cited by 1,265
Subpopulations of Mouse Blood Monocytes Differ in Maturation Stage and Inflammatory Response
Sunderkötter, C., Nikolic, T., Dillon, M. J., van Rooijen, N., Stehling, M., Drevets, D. A., & Leenen, P. J. M. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.7.4410 · Cited by 1,124
Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions
Mildner, A., Schmidt, H., Nitsche, M., Merkler, D., Hanisch, U.-K., Mack, M., Heikenwalder, M., Brück, W., Priller, J., & Prinz, M. (2007) · Nature Neuroscience · doi:10.1038/nn2015 · Cited by 1,089
Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice
Eglitis, M. A., & Mezey, É. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.8.4080 · Cited by 1,015
Fujinami, R. S., & Oldstone, M. B. A. (1985) · Science · doi:10.1126/science.2414848 · Cited by 947
Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain
Colton, C. A. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9164-4 · Cited by 916
El Khoury, J., Toft, M., Hickman, S. E., Means, T. K., Terada, K., Geula, C., & Luster, A. D. (2007) · Nature Medicine · doi:10.1038/nm1555 · Cited by 915
Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain
Alliot, F., Godin, I., & Pessac, B. (1999) · Developmental Brain Research · doi:10.1016/s0165-3806(99)00113-3 · Cited by 884
Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis
Greter, M., Heppner, F. L., Lemos, M. P., Odermatt, B. M., Goebels, N., Laufer, T., Noelle, R. J., & Becher, B. (2005) · Nature Medicine · doi:10.1038/nm1197 · Cited by 862
The role of microglia and macrophages in the pathophysiology of the CNS
Stollg, G., & Jander, S. (1999) · Progress in Neurobiology · doi:10.1016/s0301-0082(98)00083-5 · Cited by 683
Inflammation as a causative factor in the aetiology of Parkinson's disease
Whitton, P. S. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707167 · Cited by 641
Priller, J., Flügel, A., Wehner, T., Boentert, M., Haas, C. A., Prinz, M., Fernández-Klett, F., Prass, K., Bechmann, I., de Boer, B. A., et al. (2001) · Nature Medicine · doi:10.1038/nm1201-1356 · Cited by 637
Ellis, R. J., Olichney, J. M., Thal, L. J., Mirra, S. S., Morris, J. C., Beekly, D., & Heyman, A. (1996) · Neurology · doi:10.1212/wnl.46.6.1592 · Cited by 561
Origin of dendritic cells in peripheral lymphoid organs of mice
Liu, K., Waskow, C., Liu, X., Yao, K.-H., Hoh, J. J., & Nussenzweig, M. C. (2007) · Nature Immunology · doi:10.1038/ni1462 · Cited by 489
Beers, D. R., Henkel-Tigges, J., Zhao, W., Wang, J., & Appel, S. H. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807419105 · Cited by 485
King, I. L., Dickendesher, T. L., & Segal, B. M. (2009) · Blood · doi:10.1182/blood-2008-07-168575 · Cited by 444
Shaftel, S. S., Kyrkanides, S., Olschowka, J. A., Miller, J.-N. H., Johnson, R. E., & O’Banion, M. K. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31450 · Cited by 433
Blocking TGF-β–Smad2/3 innate immune signaling mitigates Alzheimer-like pathology
Town, T., Laouar, Y., Pittenger, C., Mori, T., Szekely, C. A., Tan, J., Duman, R. S., & Flavell, R. A. (2008) · Nature Medicine · doi:10.1038/nm1781 · Cited by 422
Self-citationFormation and maintenance of Alzheimer's disease β-amyloid plaques in the absence of microglia
Grathwohl, S. A., Kälin, R. E., Bolmont, T., Prokop, S., Winkelmann, G., Kaeser, S. A., Odenthal, J., Radde, R., Eldh, T., Gandy, S., et al. (2009) · Nature Neuroscience · doi:10.1038/nn.2432 · Cited by 401
Licastro, F., Pedrini, S., Caputo, L., Annoni, G., Davis, L. J., Ferri, C., Casadei, V. M., & Grimaldi, L. M. E. (2000) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(99)00226-x · Cited by 400
Hawkes, C. A., & McLaurin, J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805453106 · Cited by 397
Butovsky, O., Koronyo-Hamaoui, M., Kunis, G., Ophir, E., Landa, G., Cohen, H., & Schwartz, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604681103 · Cited by 388
T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS
Chiu, I. M., Chen, A., Zheng, Y., Kosaras, B., Tsiftsoglou, S. A., Vartanian, T. K., Brown, R. H., & Carroll, M. C. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804610105 · Cited by 380
Chakrabarty, P., Jansen‐West, K., Beccard, A., Ceballos‐Diaz, C., Levites, Y., Verbeeck, C., Zubair, A. C., Dickson, D., Golde, T. E., & Das, P. (2010) · The FASEB Journal · doi:10.1096/fj.09-141754 · Cited by 328
SHIP Represses the Generation of Alternatively Activated Macrophages
Rauh, M. J., Ho, V. W., Pereira, C. C., Sham, A. P., Sly, L. M., Lam, V., Huxham, L. A., Minchinton, A. I., Mui, A., & Krystal, G. (2005) · Immunity · doi:10.1016/j.immuni.2005.09.003 · Cited by 301
Frackowiak, J., Wisniewski, H. M., Wegiel, J., Merz, G. S., Iqbal, K., & Wang, K. C. (1992) · Acta Neuropathologica · doi:10.1007/bf00227813 · Cited by 276
Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia
Grathwohl, S. A., Kälin, R., Bolmont, T., Prokop, S., Winkelmann, G., Kaeser, S. A., Odenthal, J., Radde, R., Eldh, T., Gandy, S. E., et al. (2010) · e-Neuroforum · doi:10.1515/nf-2010-0107 · Cited by 269
Ultrastructural Studies of the Cells Forming Amyloid Fibers in Classical Plaques
Wisniewski, H. M., Węgiel, J., WANG, K. C., Kujawa, M., & Lach, B. (1989) · Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques · doi:10.1017/s0317167100029887 · Cited by 244
Shaftel, S. S., Carlson, T. J., Olschowka, J. A., Kyrkanides, S., Matousek, S. B., & O'Banion, M. K. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.1418-07.2007 · Cited by 243
Town, T., Bai, F., Wang, T., Kaplan, A. T., Qian, F., Montgomery, R. R., Anderson, J. F., Flavell, R. A., & Fikrig, E. (2009) · Immunity · doi:10.1016/j.immuni.2008.11.012 · Cited by 226
Self-citationFlaris, N. A., Densmore, T. L., Molleston, M. C., & Hickey, W. F. (1993) · Glia · doi:10.1002/glia.440070108 · Cited by 224
Boissonneault, V., Filali, M., Lessard, M., Relton, J., Wong, G., & Rivest, S. (2008) · Brain · doi:10.1093/brain/awn331 · Cited by 221
Huell, M., Strauss, S., Volk, B., Berger, M., & Bauer, J. (1995) · Acta Neuropathologica · doi:10.1007/bf00571510 · Cited by 214
CNS Infiltration of Peripheral Immune Cells: D-Day for Neurodegenerative Disease?
Rezai-Zadeh, K. P., Gate, D., & Town, T. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9166-2 · Cited by 202
Self-citationAttems, J., Jellinger, K. A., & Lintner, F. (2005) · Acta Neuropathologica · doi:10.1007/s00401-005-1064-y · Cited by 188
Invasion of Hematopoietic Cells into the Brain of Amyloid Precursor Protein Transgenic Mice
Stalder, A. K., Ermini, F., Bondolfi, L., Krenger, W., Burbach, G. J., Deller, T., Coomaraswamy, J., Staufenbiel, M., Landmann, R. M., & Jucker, M. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2545-05.2005 · Cited by 185
T-Cells in Alzheimer's Disease
Town, T., Tan, J., Flavell, R. A., & Mullan, M. (2005) · NeuroMolecular Medicine · doi:10.1385/nmm:7:3:255 · Cited by 183
Self-citationTaking Advantage of the Systemic Immune System to Cure Brain Diseases
Yong, V. W., & Rivest, S. (2009) · Neuron · doi:10.1016/j.neuron.2009.09.035 · Cited by 167
Butovsky, O., Kunis, G., Koronyo‐Hamaoui, M., & Schwartz, M. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05652.x · Cited by 167
Drevets, D. A., Dillon, M. J., Schawang, J. S., van Rooijen, N., Ehrchen, J. M., Sunderkötter, C. H., & Leenen, P. J. M. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.7.4418 · Cited by 160
Hematopoietic cells maintain hematopoietic fates upon entering the brain
Massengale, M., Wagers, A. J., Vogel, H. S., & Weissman, I. L. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050030 · Cited by 159
Graeber, M. B., Streit, W. J., Büringer, D., Sparks, D. L., & Kreutzberg, G. W. (1992) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199205000-00009 · Cited by 149
Juedes, A. E., & Ruddle, N. H. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.8.5168 · Cited by 145
Butovsky, O., Koronyo‐Hamaoui, M., Kunis, G., Ophir, E., Landa, G., Cohen, H., & Schwartz, M. (2006) · Cited by 144
Członkowska, A., Kurkowska‐Jastrzębska, I., Członkowski, A., Peter, D., & Stefano, G. B. (2002) · PubMed · Cited by 123
Kiyota, T., Yamamoto, M., Xiong, H., Lambert, M. P., Klein, W. L., Gendelman, H. E., Ransohoff, R. M., & Ikezu, T. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006197 · Cited by 114
Phagocytosis of ?/A4 amyloid fibrils of the neuritic neocortical plaques
Wisniewski, H. M., Barcikowska, M., & Kida, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00310142 · Cited by 109
Mature monocytic cells enter tissues and engraft
Kennedy, D. W., & Abkowitz, J. L. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14944 · Cited by 109
Schleicher, U., Hesse, A., & Bogdan, C. (2004) · Blood · doi:10.1182/blood-2004-05-1749 · Cited by 93
Liu, J., Gong, N., Huang, X., Reynolds, A. D., Mosley, R. L., & Gendelman, H. E. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803330 · Cited by 89
Wenkel, H., Streilein, J. W., & Young, M. J. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.10.5125 · Cited by 79
Petito, C. K., Torres-Muñoz, J., Zielger, F., & McCarthy, M. (2006) · Journal of NeuroVirology · doi:10.1080/13550280600879204 · Cited by 51
Cerebral amyloid angiopathy in Lewy body disease
Jellinger, K. A., & Attems, J. (2008) · Journal of Neural Transmission · doi:10.1007/s00702-007-0856-8 · Cited by 50
Alternative Aβ Immunotherapy Approaches for Alzheimers Disease
Town, T. (2009) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152709787847306 · Cited by 42
Self-citationMicroglia in Alzheimer's Disease and Transgenic Models
Dickson, D. W. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65416-8 · Cited by 40
Can peripheral leukocytes be used as Alzheimer’s disease biomarkers?
Rezai-Zadeh, K. P., Gate, D., Szekely, C. A., & Town, T. (2009) · Expert Review of Neurotherapeutics · doi:10.1586/ern.09.118 · Cited by 36
Self-citationWalker, W. S. G. (1999) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(98)00237-9 · Cited by 30
Cerebral and Peripheral Amyloid Phagocytes— an Old Liaison with a New Twist
Jucker, M., & Heppner, F. L. (2008) · Neuron · doi:10.1016/j.neuron.2008.06.014 · Cited by 27
[Microglia: origin and development].
Pessac, B., Godin, I., & Alliot, F. (2001) · PubMed · Cited by 23
Flagged first, then by citations
Cited by
Sorted by citations
Microglia development follows a stepwise program to regulate brain homeostasis
Matcovitch-Natan, O., Winter, D. R., Giladi, A., Vargas Aguilar, S., Spinrad, A., Sarrazin, S., Ben-Yehuda, H., David, E., Zelada González, F., Perrin, P., et al. (2016) · Science · doi:10.1126/science.aad8670 · Cited by 1,180
Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases
Yuan, J., Amin, P., & Ofengeim, D. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0093-1 · Cited by 967
Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease
Jay, T. R., Hirsch, A. M., Broihier, M. L., Miller, C. M., Neilson, L. E., Ransohoff, R. M., Lamb, B. T., & Landreth, G. E. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2110-16.2016 · Cited by 457
Inflammatory process in Alzheimer's Disease
Meraz-Ríos, M. A., Toral-Rios, D., Franco-Bocanegra, D., Villeda-Hernández, J., & Campos-Peña, V. (2013) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2013.00059 · Cited by 427
Baruch, K., Deczkowska, A., Rosenzweig, N., Tsitsou-Kampeli, A., Sharif, A. M., Matcovitch-Natan, O., Kertser, A., David, E., Amit, I., & Schwartz, M. (2016) · Nature Medicine · doi:10.1038/nm.4022 · Cited by 425
Metadata
- Authors
- Gate, D., Rezai-Zadeh, K., Jodry, D., Rentsendorj, A., & Town, T.
- Affiliations
- Cedars-Sinai Medical Center (US)
- Corresponding author
- Town, Terrence
- Venue
- Journal of Neural Transmission
- Published
- 2010-06-02
- Volume
- 117
- Issue
- 8
- Pages
- 961-970
- ISSN
- 0300-9564 (ISSN-L)
- 1435-1463
- PMC
- PMC2917548
- OpenAlex
- W2058092975
- Cited by
- 107
- References
- 69
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 12 · 2023: 5 · 2022: 8 · 2021: 4 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 10 · 2015: 12 · 2014: 8 · 2013: 6 · 2012: 7
- FWCI
- 0.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Journal of Neural Transmission (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Case Western Reserve University
- University of South Florida
- National Institutes of Health
- National Institute on Aging (R00AG029726)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, macrophages, microglia, amyloid-beta, amyloid plaques, cerebral amyloidosis, cell of origin, therapeutic targeting, neuroinflammation
- MeSH terms
- Alzheimer Disease, Animals, Blood-Brain Barrier, Brain, Humans, Macrophages, Models, Biological
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
