Migration of neutrophils targeting amyloid plaques in Alzheimer's disease mouse model
Open accessAbstract
Immune responses in the brain are thought to play a role in disorders of the central nervous system, but an understanding of the process underlying how immune cells get into the brain and their fate there remains unclear. In this study, we used a 2-photon microscopy to reveal that neutrophils infiltrate brain and migrate toward amyloid plaques in a mouse model of Alzheimer's disease. These findings suggest a new molecular process underlying the pathophysiology of Alzheimer's disease.
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Neutrophils modulate Alzheimer's disease pathology.
“neutrophils have been shown to modulate Alzheimer’s disease pathology [52, 53].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [52]
The Introduction and Results (page numbers unavailable) show that neutrophils migrate toward amyloid plaques in an Alzheimer’s disease mouse model. The Discussion (page number unavailable) says they might influence disease progression, but whether they are protective or detrimental remains unknown. The paper therefore does not show that neutrophils modulate pathology, as the citing sentence states. (LLM, conf=0.88)
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Self-citationThe emerging role of neutrophils in neurodegeneration
Rossi, B., Constantin, G., & Zenaro, E. (2019) · Immunobiology · doi:10.1016/j.imbio.2019.10.014 · Cited by 59 · see citing works
Zou, C., Mifflin, L., Hu, Z., Zhang, T., Shan, B., Wang, H., Xing, X., Zhu, H., Adiconis, X., Levin, J. Z., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108447 · Cited by 59 · see citing works
Genetic Approaches Using Zebrafish to Study the Microbiota–Gut–Brain Axis in Neurological Disorders
Lee, J. G., Cho, H.-J., Jeong, Y.-M., & Lee, J.-S. (2021) · Cells · doi:10.3390/cells10030566 · Cited by 55 · see citing works
Self-citationAssociation of peripheral immunity with cognition, neuroimaging, and Alzheimer’s pathology
Hou, J., Ou, Y., Xu, W., Zhang, P., Tan, L., Yu, J., & Initiative, O. B. O. A. D. N. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-00968-y · Cited by 55 · see citing works
“Previous articles have investigated the association of peripheral immunity with AD, but they were limited to basic research [5, 6], animal research [18, 19, 30], review [26, 40, 42], and rough cross-sectional analyses [7], and most studies were of small samples [28, 33, 36, 44, 51, 56, 57].”
BackgroundBang, S., Lee, S., Choi, N., & Kim, H. N. (2021) · Advanced Healthcare Materials · doi:10.1002/adhm.202002119 · Cited by 55 · see citing works
Ramos-Cejudo, J., Johnson, A. D., Beiser, A., Seshadri, S., Salinas, J., Berger, J. S., Fillmore, N. R., Do, N., Zheng, C., Kovbasyuk, Z., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.773984 · Cited by 49 · see citing works
Imaging of Leukocyte Trafficking in Alzheimer’s Disease
Pietronigro, E. C., Zenaro, E., & Constantin, G. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00033 · Cited by 52 · see citing works
“However, recent TPLSM studies have shown that circulating leukocytes migrate into the brain parenchyma of AD mice, revealing previously unknown mechanisms of AD pathogenesis and helping to identify new therapeutic strategies for AD (19, 20).”
BackgroundA quadrupolar two-photon fluorescent probe for in vivo imaging of amyloid-β plaques
Heo, C. H., Sarkar, A. R., Baik, S. H., Jung, T. S., Kim, J. J., Kang, H., Mook‐Jung, I., & Kim, H. M. (2016) · Chemical Science · doi:10.1039/c6sc00355a · Cited by 53 · see citing works
Self-citationShi, J., Peng, H. Y., You, S., Liu, Y., Xu, J., Xu, Y., Liu, H., Shi, R., Cao, Y., & Liu, C. (2018) · European Journal of Neurology · doi:10.1111/ene.13575 · Cited by 53 · see citing works
“Recent studies demonstrated that neutrophils can enter brain tissues that other white blood cells cannot penetrate [30,31].”
BackgroundWu, C., Bawa, K. K., Ouk, M., Leung, N., Yu, D., Lanctôt, K. L., Herrmann, N., Pakosh, M. T., & Swardfager, W. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101130 · Cited by 53 · see citing works
Guo, Y., Zeng, H., & Chen, G. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/9931742 · Cited by 53 · see citing works
“Studies have shown that neutrophil depletion can improve the cognitive function and reduce AD-associated pathological damage in AD model mice [56, 57].”
BackgroundNeutrophils as emerging protagonists and targets in chronic inflammatory diseases
Rawat, K., & Shrivastava, A. (2022) · Inflammation Research · doi:10.1007/s00011-022-01627-6 · Cited by 50 · see citing works
“Various clinical and animal studies have shown that neutrophils may translocate to the cerebral blood vessels and co-localize with amyloid plaques within the brain parenchyma [56].”
BackgroundShi, M., Chu, F., Zhu, F., & Zhu, J. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-023-03003-5 · Cited by 50 · see citing works
“More than a decade ago, Baik, et al. have observed the peripheral neutrophils infiltrating into the brains of both AD patients and its Tg models (5xFAD and 3xTg-AD mice), and existing in the areas with Aβ deposits [71, 72].”
BackgroundUltrathin Dual‐Scale Nano‐ and Microporous Membranes for Vascular Transmigration Models
Salminen, A. T., Zhang, J., Madejski, G. R., Khire, T. S., Waugh, R. E., McGrath, J. L., & Gaborski, T. R. (2019) · Small · doi:10.1002/smll.201804111 · Cited by 50 · see citing works
Wyatt-Johnson, S. K., & Brutkiewicz, R. R. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.592359 · Cited by 50 · see citing works
“, 2020), neutrophils (Baik et al., 2014; Zenaro et al., 2015; Vida et al., 2017; Park et al., 2019), NK cells (Marsh et al.”
BackgroundPark, J., Baik, S. H., Mook‐Jung, I., Irimia, D., & Cho, H. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02231 · Cited by 46 · see citing works
“Among them, neutrophils are the body’s most abundant and frontline immune cells, respond with both central and peripheral immune effectors during the progression of AD (17).”
BackgroundSelf-citationKretzschmar, G. C., Bumiller‐Bini, V., Filho, M. A. G., Zonta, Y. R., Yu, K. S. T., de Souza, R. L. R., Dias‐Melicio, L. A., & Boldt, A. B. W. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.630869 · Cited by 42 · see citing works
Page, A. Y. L., Lamoureux, J., Bourgade, K., Frost, E. H., Pawelec, G., Witkowski, J. M., Larbi, A., Dupuis, G., & Fülöp, T. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170124 · Cited by 42 · see citing works
Cellular transcriptional alterations of peripheral blood in Alzheimer’s disease
Song, L., Yang, Y., Guo, Q., & Zhao, X. (2022) · BMC Medicine · doi:10.1186/s12916-022-02472-4 · Cited by 38 · see citing works
“Consistent with the extravasation migration of neutrophils into brain [31, 36], we observed that the absolute abundance of neutrophils was significantly increased in AD brains in both cerebellum (CBE) (P = 4.”
BackgroundXia, X., He, X., Zhao, T., Yang, J., Bi, Z., Fu, Q., Liu, J., Ao, D., Wei, Y., & Wei, X. (2023) · Cell Proliferation · doi:10.1111/cpr.13529 · Cited by 38 · see citing works
Neutrophils in animal models of autoimmune disease
Németh, T., Mócsai, A., & Lowell, C. A. (2016) · Seminars in Immunology · doi:10.1016/j.smim.2016.04.001 · Cited by 39 · see citing works
The Role of Sphingolipids and Specialized Pro-Resolving Mediators in Alzheimer’s Disease
de Wit, N. M., Mol, K., Rodríguez‐Lorenzo, S., de Vries, H. E., & Kooij, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.620348 · Cited by 39 · see citing works
Barkaway, A., Attwell, D., & Korte, N. (2022) · Neurophotonics · doi:10.1117/1.nph.9.3.031914 · Cited by 37 · see citing works
“Nils Korte studied physiology in Glasgow and Melbourne, and did his PhD at University College London on the regulation of CBF in health, stroke, and AD.”
BackgroundInfluentialMain, E. N., Cruz, T. M., & Bowlin, G. L. (2023) · Regenerative Biomaterials · doi:10.1093/rb/rbad070 · Cited by 35 · see citing works
Inflammatory pathway analytes predicting rapid cognitive decline in MCI stage of Alzheimer’s disease
Pillai, J. A., Bena, J., Bebek, G., Bekris, L. M., Bonner‐Jackson, A., Kou, L., Pai, A., Sørensen, L., Neilsen, M., Rao, S. M., et al. (2020) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51109 · Cited by 34 · see citing works
Changes in the structure and function of the brain years after Pre-eclampsia
Ijomone, O. K., Shallie, P. D., & Naicker, T. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.06.006 · Cited by 32 · see citing works
Unzeta, M., Hernández‐Guillamón, M., Sun, P., & Solé, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073365 · Cited by 33 · see citing works
PET Imaging of Neutrophils Infiltration in Alzheimer's Disease Transgenic Mice
Kong, Y., Liu, K., Hua, T., Zhang, C., Sun, B., & Guan, Y. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.523798 · Cited by 30 · see citing works
“In the transgenic AD model mice brain, there is also substantial neutrophil infiltration to Aβ plaques, and neutrophil depletion or trafficking inhibition can reduce the AD-like neuropathology and improve the cognitive dysfunction (10, 11).”
BackgroundThe role of integrins in brain health and neurodegenerative diseases
Cui, Y., Rõlova, T., & Fagerholm, S. C. (2024) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2024.151441 · Cited by 30 · see citing works
Alzheimer’s disease: The role of T lymphocytes in neuroinflammation and neurodegeneration
Asamu, M. O., Oladipo, O. O., Abayomi, O. A., & Adebayo, A. A. (2023) · Brain Research · doi:10.1016/j.brainres.2023.148589 · Cited by 31 · see citing works
A Brief Overview of Neutrophils in Neurological Diseases
Chakraborty, S., Tabrizi, Z., Bhatt, N. N., Franciosa, S. A., & Bracko, O. (2023) · Biomolecules · doi:10.3390/biom13050743 · Cited by 28 · see citing works
Myeloid cells in vascular dementia and Alzheimer's disease: Possible therapeutic targets?
García‐Culebras, A., Cuartero, M. I., Peña‐Martínez, C., Moraga, A., Vázquez‐Reyes, S., Castro-Millán, F. J., Cortés‐Canteli, M., Lizasoaín, I., & Moro, M. Á. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16159 · Cited by 27 · see citing works
“In this sense, different studies in AD patients have clearly demonstrated that neutrophils infiltrate into the brain parenchyma (Baik et al., 2014; Zenaro et al., 2015).”
BackgroundResultXia, H., Feng, Y., Zhu, H., Yang, D., Wang, C., Wang, Z., Zhang, H., Pan, W., Zhao, Y., Initiative, A. D. N., et al. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03432-1 · Cited by 27 · see citing works
“Further longitudinal human trials and animal studies are warranted to validate our fi ndings and elucidate the underlying molecular mechanisms.”
Immune dysfunction in Alzheimer disease
Butovsky, O., Rosenzweig, N., Kleemann, K. L., Jorfi, M., Kuchroo, V. K., Tanzi, R. E., & Weiner, H. L. (2025) · Nature reviews. Neuroscience · doi:10.1038/s41583-025-00997-0 · Cited by 34 · see citing works
“Neutrophils are another myeloid cell type that interacts with the brain borders and have been shown to infiltrate the brains of people with AD 50,129 and AD mouse models 130,131 .”
Panayiotou, E., Fella, E., Andreou, S., Papacharalambous, R., Gerasimou, P., Costeas, P., Angeli, S., Kousiappa, I., Papacostas, S., & Kyriakides, T. (2019) · PLoS ONE · doi:10.1371/journal.pone.0225417 · Cited by 26 · see citing works
“A neutrophil/monocyte marker (Ly6C/G) has been found on cells migrating towards Aβ plaques in an AD mouse model [26].”
BackgroundIs Targeting the Inflammasome a Way Forward for Neuroscience Drug Discovery?
Swanton, T., Cook, J., Beswick, J. A., Freeman, S., Lawrence, C. B., & Brough, D. (2018) · SLAS DISCOVERY · doi:10.1177/2472555218786210 · Cited by 25 · see citing works
Interleukin 22 and its association with neurodegenerative disease activity
Chen, W., Wang, J., Yang, H., Sun, Y., Chen, B., Liu, Y., Han, Y., Shan, M., & Zhan, J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.958022 · Cited by 25 · see citing works
Qi, F., Zuo, Z., Hu, K., Wang, R., Wu, T., Liu, H., Tang, J., Wang, Q., Xie, Y., Tan, L., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02097-w · Cited by 23 · see citing works
“Neutrophils are the key effector cells of early innate immunity and contribute to in fl ammation in the brain [10, 56] and periphery [6].”
BackgroundJacobs, T., Jacobson, S. R., Fortea, J., Berger, J. S., Vedvyas, A., Marsh, K., He, T., Gutiérrez‐Jiménez, E., Fillmore, N. R., Gonzalez, M., et al. (2024) · Immunity & Ageing · doi:10.1186/s12979-024-00435-2 · Cited by 26 · see citing works
“This was done for both cohorts: the ADNI ( A ) and NYU ( B ) considered an immune-privileged site, neutrophils and NETs have been shown to aggregate in the cerebral small vessels of AD patients, particularly near Aβ plaques and tau tangles [7, 8, 56].”
BackgroundMethodKatayama, H. (2019) · Brain and Behavior · doi:10.1002/brb3.1504 · Cited by 23 · see citing works
“Studies using 2-photon microscopy revealed substantial neutrophil migration toward Aβ plaques in transgenic AD mice brain model (Baik et al., 2014; Zenaro et al., 2015).”
BackgroundCD8+ T cells exacerbate AD-like symptoms in mouse model of amyloidosis
Wang, X., Campbell, B., Bodogai, M., McDevitt, R. A., Patrikeev, A., Gusev, F. E., Ragonnaud, E., Kumaraswami, K., Shirenova, S. D., Vardy, K., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.08.045 · Cited by 25 · see citing works
Neutrophils: a subgroup of neglected immune cells in ALS
Cao, W., & Fan, D. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1246768 · Cited by 23 · see citing works
“showed dynamic imaging of neutrophils entering into brain parenchyma in AD mice, but no such migration was found in wild-type mice (46).”
BackgroundNetzahualcoyotzi, C., Santillán‐Cigales, J. J., Adalid-Peralta, L. V., & Velasco, I. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16106 · Cited by 22 · see citing works
“Of note is the fact that neutrophils migrate toward A β plaques, suggesting a direct role of this peptide in neutrophil recruitment during AD (Baik et al., 2014 ; Zenaro et al., 2015).”
IL-22, a vital cytokine in autoimmune diseases
Li, J., Wu, Z., Wu, Y., Hu, X., Yang, J., Zhu, D., Wu, M., Li, X., Bentum‐Ennin, L., & Hu, W. (2024) · Clinical & Experimental Immunology · doi:10.1093/cei/uxae035 · Cited by 21 · see citing works
- Authors
- Baik, S. H., Cha, M.-Y., Hyun, Y.-M., Cho, H., Hamza, B., Kim, D. K., Han, S.-H., Choi, H., Kim, K. H., Moon, M., Lee, J., Kim, M., Irimia, D., & Mook-Jung, I.
- Affiliations
- Seoul National University (KR)
- University of Rochester Medicine (US)
- Harvard University (US)
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 35
- Issue
- 6
- Pages
- 1286-1292
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC4248665
- OpenAlex
- W2023641365
- Cited by
- 181
- References
- 19
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 26 · 2023: 17 · 2022: 22 · 2021: 16 · 2020: 16 · 2019: 10 · 2018: 13 · 2017: 13 · 2016: 9 · 2015: 11 · 2014: 3
- FWCI
- 6.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Research Foundation of Korea (2012R1A2A1A01002881)
- MRC (2011–0030738)
- Korea National Institute of Health ROAD R&D Program Project (A092058)
- Korea Institute of Science and Technology Institutional Program (2E24242-13–135)
- Cooperative Research Program for Agriculture Science & Technology Development (PJ009103)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- neutrophils, amyloid plaques, Alzheimer's disease, neutrophil migration, brain immune response, neuroinflammation, two-photon microscopy, mouse model
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cell Movement, Cells, Cultured, Disease Models, Animal, Humans, Mice, Transgenic, Microscopy, Neutrophils, Mice, Molecular Imaging, Plaque, Amyloid
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