Progranulin is a chemoattractant for microglia and stimulates their endocytic activity
Open accessAbstract
Mutations resulting in progranulin haploinsufficiency cause disease in patients with a subset of frontotemporal lobar degeneration; however, the biological functions of progranulin in the brain remain unknown. To address this subject, the present study initially assessed changes in gene expression and cytokine secretion in rat primary cortical neurons treated with progranulin. Molecular pathways enriched in the progranulin gene set included cell adhesion and cell motility pathways and pathways involved in growth and development. Secretion of cytokines and several chemokines linked to chemoattraction but not inflammation were also increased from progranulin-treated primary neurons. Therefore, whether progranulin is involved in recruitment of immune cells in the brain was investigated. Localized lentiviral expression of progranulin in C57BL/6 mice resulted in an increase of Iba1-positive microglia around the injection site. Moreover, progranulin alone was sufficient to promote migration of primary mouse microglia in vitro. Primary microglia and C4B8 cells demonstrated more endocytosis of amyloid β1-42 when treated with progranulin. These data demonstrate that progranulin acts as a chemoattractant in the brain to recruit or activate microglia and can increase endocytosis of extracellular peptides such as amyloid β.
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Mutations leading to haplo-insufficiency of GRN produce FTD syndromes characterized by TDP-43 pathology.
“Furthermore, mutations leading to haplo-insufficiency of GRN, a growth factor that has peripheral immune and central microglial regulatory functions (Petkau et al., 2010; Yin et al., 2010; Pickford et al., 2011), produce FTD syndromes characterized by TDP-43 pathology.”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Pickford et al., 2011
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Implications of Microglia in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
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Mechanisms of Granulin Deficiency: Lessons from Cellular and Animal Models
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NG2/CSPG4 and progranulin in the posttraumatic glial scar
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Microglia gone awry: linking immunometabolism to neurodegeneration
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Progranulin Reduction Is Associated With Increased Tau Phosphorylation in P301L Tau Transgenic Mice
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“A previous study showed that PGRN acts as a chemotactic factor for microglia and PGRN-treated microglia exhibit an enhanced capacity to phagocytose Aβ1–42 [27].”
Glial TDP‐43 and TDP‐43 induced glial pathology, focus on neurodegenerative proteinopathy syndromes
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The microglial lysosomal system in Alzheimer’s disease: Guardian against proteinopathy
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Asymmetric pathology in primary progressive aphasia with progranulin mutations and TDP inclusions
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Townley, R. A., Boeve, B. F., & Benarroch, E. E. (2017) · Neurology · doi:10.1212/wnl.0000000000004840 · Cited by 39 · see citing works
Progranulin in neurodegenerative dementia
Wang, X., Zeng, P. H., Fang, Y., Zhang, T., & Tian, Q. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15378 · Cited by 38 · see citing works
Petkau, T. L., Hill, A., & Leavitt, B. R. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.12.006 · Cited by 36 · see citing works
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Microglia in Alzheimer’s Disease: An Unprecedented Opportunity as Prospective Drug Target
Kulkarni, B., Martins, N. A., & Kumar, D. (2022) · Molecular Neurobiology · doi:10.1007/s12035-021-02661-x · Cited by 36 · see citing works
The Role of Progranulin (PGRN) in the Pathogenesis of Ischemic Stroke
Purrahman, D., Shojaeian, A., Poniatowski, Ł. A., Piechowski‐Jóźwiak, B., & Mahmoudian‐Sani, M. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01396-8 · Cited by 30 · see citing works
“With regard to microglia, PGRN has a special ability that is recruiting or activating it through chemoattractants (Pickford et al. 2011).”
BackgroundDissecting the role of sortilin receptor signaling in neurodegeneration induced by NGF deprivation
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“The increase of Ab in aged Sort1 / mice could be explained by the broad actions of sortilin, acting not only as a receptor for proNGF but also for neurotensin [20] and progranulin [21], both of which are suggested to play a neuroprotective role [22,23].”
Batzu, L., Westman, E., & Pereira, J. B. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.12.012 · Cited by 30 · see citing works
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Defects of Nutrient Signaling and Autophagy in Neurodegeneration
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Progranulin promotes activation of microglia/macrophage after pilocarpine-induced status epilepticus
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The role of efferocytosis in neuro-degenerative diseases
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The Role of PGRN in Alzheimer’s Disease
Jing, H., Tan, M., Yu, J., & Tan, L. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9358-0 · Cited by 25 · see citing works
Potential Mechanisms of Progranulin-deficient FTLD
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“Despite the fact that microglia express very low levels of sortilin, they have a robust signaling response to PGRN and are able to migrate toward a PGRN source in vitro and in vivo (Pickford et al. 2011).”
Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations
Kashyap, S. N., Boyle, N. R., & Roberson, E. D. (2023) · Neurotherapeutics · doi:10.1007/s13311-023-01348-6 · Cited by 21 · see citing works
Lipotoxic Injury Differentially Regulates Brain Microvascular Gene Expression in Male Mice
Nuthikattu, S., Milenković, D., Rutledge, J. C., & Villablanca, A. C. (2020) · Nutrients · doi:10.3390/nu12061771 · Cited by 21 · see citing works
Guan, Z., Chen, Z., Fu, S., Dai, L., & Shen, Y. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00260 · Cited by 21 · see citing works
Progranulin haploinsufficiency reduces amyloid beta deposition in Alzheimer’s disease model mice
Hosokawa, M., Tanaka, Y., Arai, T., Kondo, H., Akiyama, H., & Hasegawa, M. (2017) · EXPERIMENTAL ANIMALS · doi:10.1538/expanim.17-0060 · Cited by 20 · see citing works
A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses
Du, H., Wong, M. Y., Zhang, T., Santos, M. N., Hsu, C., Zhang, J., Yu, H., Luo, W., & Hu, F. (2021) · Life Science Alliance · doi:10.26508/lsa.202000874 · Cited by 19 · see citing works
Yu, T., Lin, Y., Xu, Y., Dou, Y., Wang, F., Quan, H., Zhao, Y., & Liu, X. (2020) · Neural Plasticity · doi:10.1155/2020/8855822 · Cited by 18 · see citing works
RetractedB Lymphocytes in Alzheimer’s Disease—A Comprehensive Review
Plantone, D., Pardini, M., Locci, S., Nobili, F. M., & Stefano, N. D. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220261 · Cited by 18 · see citing works
“Progranulin has a complex role in neuroinflamma-tion and may act as a chemoattractant for microglia in CNS and promote the neuronal secretion of inter-leukins that induce differentiation of microglia into an anti-inflammatory phenotype [175, 176].”
Rollinson, S. J., Young, K., Callister, J. B., & Pickering-Brown, S. M. (2016) · European Journal of Neuroscience · doi:10.1111/ejn.13297 · Cited by 16 · see citing works
Amyloid-Beta-Activated Human Microglial Cells Through ER-Resident Proteins
Yoo, Y., Byun, K., Kang, T., Bayarsaikhan, D., Kim, J. Y., Oh, S., Kim, Y. H., Kim, S. Y., Chung, W., Kim, S. U., et al. (2014) · Journal of Proteome Research · doi:10.1021/pr500926r · Cited by 17 · see citing works
Microglia increases the proliferation of retinal precursor cells during postnatal development.
Kuse, Y., Ohuchi, K., Nakamura, S., Hara, H., & Shimazawa, M. (2018) · Europe PMC (PubMed Central) · Cited by 17 · see citing works
Shahbaz, S. K., Koushki, K., Hedayati, S. K., McCloskey, A. P., Kesharwani, P., Naderi, Y., & Sahebkar, A. (2024) · Medicinal Research Reviews · doi:10.1002/med.22064 · Cited by 15 · see citing works
Takahashi, K., Nakamura, S., Otsu, W., Shimazawa, M., & Hara, H. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02203-1 · Cited by 15 · see citing works
Frontotemporal Lobar Degeneration
Galimberti, D., & Scarpini, E. A. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-407824-6.00006-9 · Cited by 15 · see citing works
Progranulin regulates neurogenesis in the developing vertebrate retina
Walsh, C. E., & Hitchcock, P. F. (2017) · Developmental Neurobiology · doi:10.1002/dneu.22499 · Cited by 13 · see citing works
Progranulin regulates the development and function of NKT2 cells through EZH2 and PLZF
Du, Z., Huang, L., Dai, X., Yang, D., Niu, L., Miller, H., Ruan, C., Li, H., Hu, L., Zhou, L., et al. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-00973-6 · Cited by 12 · see citing works
Suh, H.-S., Gelman, B. B., & Lee, S. C. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9495-z · Cited by 12 · see citing works
AAV-GRN partially corrects motor deficits and ALS/FTLD-related pathology in Tmem106b−/−Grn−/− mice
Feng, T., Minevich, G., Liu, P., Qin, H. X., Wozniak, G. G., Pham, J., Pham, K., Korgaonkar, A. A., Kurnellas, M., Defranoux, N. A., et al. (2023) · iScience · doi:10.1016/j.isci.2023.107247 · Cited by 11 · see citing works
Wang, Z., He, Q., Zhang, X., Ma, Y., Fan, F., Dong, Y., Xu, W., Yin, Y., & He, Y. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02952 · Cited by 11 · see citing works
Relevance of raised cerebrospinal fluid monocyte levels in patients with frontotemporal dementia
Pawlowski, M., Lueg, G., Groß, C. C., Johnen, A., Krämer, J., Weckesser, M., Wiendl, H., Meuth, S. G., & Duning, T. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.09.032 · Cited by 10 · see citing works
Cysteine-rich granulin-3 rapidly promotes amyloid-β fibrils in both redox states
Bhopatkar, A. A., Ghag, G., Wolf, L. M., Dean, D. N., Moss, M. A., & Rangachari, V. (2019) · Biochemical Journal · doi:10.1042/bcj20180916 · Cited by 9 · see citing works
Körtvélyessy, P., Huchtemann, T., Heinze, H., & Bittner, D. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18030490 · Cited by 9 · see citing works
Progranulin function and regulation in the CNS
Life, B. E., & Leavitt, B. R. (2025) · Trends in Neurosciences · doi:10.1016/j.tins.2025.05.004 · Cited by 8 · see citing works
The role of progranulin in ischemic heart disease and its related risk factors
Alyahya, A. M. (2022) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2022.106215 · Cited by 8 · see citing works
Naumnik, W., Panek, B., Ossolińska, M., & Naumnik, B. (2018) · Advances in experimental medicine and biology · doi:10.1007/5584_2018_285 · Cited by 7 · see citing works
Nasir, A. R., & Nouh, C. D. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1671419 · Cited by 8 · see citing works
“Genetic mutations beyond those in the TARDBP gene have also been linked to TDP-43 pathology, particularly C9Orf72 and GNR, and can serve as a common ground for some of these processes (Pickford et al., 2011; O’Rourke et al., 2016; Pottier et al., 2019; Kahriman et al., 2023).”
Eckstein, M., Lieb, V., Jung, R., Sikic, D., Weigelt, K., Stöhr, R., Geppert, C. I., Weyerer, V., Bertz, S., Serrero, G., et al. (2021) · Cells · doi:10.3390/cells10071796 · Cited by 6 · see citing works
GRN Missense Variants and Familial Alzheimer’s Disease: Two Case Reports
Ingannato, A., Bessi, V., Chiari, A., Salvatori, D., Bagnoli, S., Bedin, R., Ferrari, C., Sorbi, S., & Nacmias, B. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230689 · Cited by 6 · see citing works
Horinokita, I., Hayashi, H., Yoshizawa, R., Ichiyanagi, M., Imamura, Y., Iwatani, Y., & Takagi, N. (2021) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2021.103625 · Cited by 5 · see citing works
Genetics of Frontotemporal Dementia
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Increased Fat Taste Preference in Progranulin-Deficient Mice
Schumann, L., Wilken‐Schmitz, A., Trautmann, S., Vogel, A., Schreiber, Y., Hahnefeld, L., Gurke, R., Geißlinger, G., & Tegeder, I. (2021) · Nutrients · doi:10.3390/nu13114125 · Cited by 4 · see citing works
“In the periphery, progranulin reduces inflammation [7,8] by increasing the phagocytosis activity of myeloid immune cells [9,10] and possibly via anti-TNF signalling [11,12].”
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“Specifically, PGRN regulates lysosomal activity and inflammation in plaque-associated microglia, and it can promote microglial endocytosis of Aβ peptides and phagocytosis of Aβ plaques [78–80].”
Progranulin and Inflammation‐Induced Cancer: An Important Player in the Tumor Microenvironment?
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“In vivo evidence has shown that microglia produce and upregulate PGRN in response to injury, and lentiviral overexpression of human PGRN increases Iba1⁺ microglial density (Pickford et al. 2011).”
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Extracellular chaperones in lysosomal storage diseases
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Frontotemporal Lobar Degeneration: Genetics and Clinical Phenotypes
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Factors in glutamate excitotoxicity, inflammation and epilepsy
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- Authors
- Pickford, F., Marcus, J., Camargo, L. M., Xiao, Q., Graham, D., Mo, J.-R., Burkhardt, M., Kulkarni, V., Crispino, J., Hering, H., & Hutton, M.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Pickford, Fiona
- ORCID
- Camargo, Luiz Miguel
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 178
- Issue
- 1
- Pages
- 284-295
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC3070582
- OpenAlex
- W2155939544
- Cited by
- 107
- References
- 56
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 2 · 2023: 5 · 2022: 6 · 2021: 10 · 2020: 8 · 2019: 10 · 2018: 7 · 2017: 12 · 2016: 2 · 2015: 10 · 2014: 12 · 2013: 5 · 2012: 4
- FWCI
- 4.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- progranulin, microglia, chemoattraction, microglial migration, endocytosis, amyloid-beta, frontotemporal lobar degeneration, chemokines, cytokines, cortical neurons, Iba1
- MeSH terms
- Progranulins, Animals, Brain, Calcium-Binding Proteins, Cell Movement, Chemotactic Factors, Endocytosis, Humans, Mice, Mutant Strains, Microfilament Proteins, Neurons, Cytokines, Microglia, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Mice, Rats
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