Abstract
Granulocyte–monocyte colony-stimulating factor (GM-CSF) is a member of the hematopoietic growth factor family, promoting proliferation and differentiation of hematopoietic progenitor cells of the myeloid lineage. In recent years, GM-CSF has also proved to be an important neurotrophic factor in the central nervous system (CNS) via binding to the GM-CSF receptor (GM-CSF R). Furthermore, studies on rodent CNS revealed a wide distribution of both the major binding α-subunit of the GM-CSF R (GM-CSF Rα) and its ligand. Since respective data on the expression pattern of these two molecules are still lacking, the present study has been designed to systematically analyze the protein expression of GM-CSF and GM-CSF Rα in the human brain, with particular emphasis on their regulation in Alzheimer’s disease (AD). One major finding is that both GM-CSF and GM-CSF Rα were ubiquitously but not uniformly expressed in neurons throughout the CNS. Protein expression of GM-CSF and GM-CSF Rα was not restricted to neurons but also detectable in astrocytes, ependymal cells and choroid plexus cells. Interestingly, distribution and intensity of immunohistochemical staining for GM-CSF did not differ among AD brains and age-matched controls. Concerning GM-CSF Rα, a marked reduction of protein expression was predominantly detected in the hippocampus although a slight reduction was also found in various cortical regions, thalamic nuclei and some brainstem nuclei. Since the hippocampus is one of the target regions of neurodegenerative changes in AD, reduction of GM-CSF Rα, with consecutive downregulation of GM-CSF signaling, may contribute to in the progressive course of neurodegeneration in AD.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arima K, Nakamura M, Sunohara N, Nishio T, Ogawa M, Hirai S, Kawai M, Ikeda K (1999) Immunohistochemical and ultrastructural characterization of neuritic clusters around ghost tangles in the hippocampal formation in progressive supranuclear palsy brains. Acta Neuropathol 97:565–576
Armstrong RA, Lantos PL, Cairns NJ (2008) What determines the molecular composition of abnormal protein aggregates in neurodegenerative disease? Neuropathology 28:351–365
Baldwin GC, Benveniste EN, Chung GY, Gasson JC, Golde DW (1993) Identification and characterization of a high-affinity granulocyte–macrophage colony-stimulating factor receptor on primary rat oligodendrocytes. Blood 82:3279–3282
Bancher C, Grundke-Iqbal I, Iqbal K, Fried VA, Smith HT, Wisniewski HM (1991) Abnormal phosphorylation of tau precedes ubiquitination in neurofibrillary pathology of Alzheimer’s disease. Brain Res 539:11–18
Bouhy D, Malgrange B, Multon S, Poirrier A-L, Scholtes F, Schoenen J, Franzen R (2006) Dealyed GM-CSF treatment stimulates axonal regeneration and functional recovery in paraplegic rats via an increased BDNF expression by endogenous macrophages. FASEB J 20:E493–E502
Boyd TD, Bennett SP, Mori T, Governatori N, Runfeldt M, Norden M, Padmanabhan J, Neame P, Wefes I, Sanchez-Ramos J, Arendash GW, Potter H (2010) GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. J Alzheimers Dis 21:505–518
Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404
Bruno E, Luikart SD, Long MW, Hoffman R (1995) Marrow-derived heparan sulfate proteoglycan mediates the adhesion of hematopoietic cells to cytokines. Exp Hematol 23:1212–1217
Dame JB, Christensen RD, Juul SE (1999) The distribution of granulocyte–macrophage colony-stimulating factor and its receptor in the developing human fetus. Pediatr Res 46:358–366
Goedert M, Jakes R, Vanmechelen E (1995) Monoclonal antibody AT8 recognises tau protein phosphorylated at both serine 202 and threonine 205. Neurosci Lett 189:167–169
Guillemin G, Boussin FD, Le Grand R, Croitoru J, Coffigny H, Dormont D (1996) Granulocyte macrophage colony stimulating factor stimulates in vitro proliferation of astrocytes derived from simian mature brains. Glia 16:71–80
Ha Y, Kim YS, Cho JM, Yoon SH, Park SR, Yoon do H, Kim EY, Park HC (2005) Role of granulocyte–macrophage colony-stimulating factor in preventing apoptosis and improving functional outcome in experimental spinal cord contusion injury. J Neurosurg Spine 2:55–61
Hercus TR, Thomas D, Guthridge MA, Ekert PG, King-Scott J, Parker MW, Lopez AF (2009) The granulocyte–macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood 114:1289–1298
Kim NK, Choi BH, Huang X, Snyder BJ, Bukhari S, Kong T-H, Park H, Park HC, Park SR, Ha Y (2009) Granulocyte–macrophage colony-stimulating factor promotes survival of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced murine Parkinson’s disease model. Eur J Neurosci 29:891–900
Kong TH, Choi J-K, Park H, Choi BH, Snyder BJ, Bukhari S, Kim N-K, Huang X, Park SR, Park HC, Ha Y (2009) Reduction in programmed cell death and improvement in functional outcome of transient focal cerebral ischemia after administration of granulocyte–macrophage colony-stimulating factor. J Neurosurg 111:155–163
Krüger C, Laage R, Pitzer C, Schäbitz W-R, Schneider A (2007) The hematopoietic factor GM-CSF (granulocyte–macrophage colony-stimulating factor) promotes neuronal differentiation of adult neural stem cells in vitro. BMC Neurosci 8:88
Maurer MH, Schäbitz W-R, Schneider A (2008) Old friends in new constellations—the hematopoetic growth factors G-CSF, GM-CSF, and EPO for the treatment of neurological diseases. Curr Med Chem 15:1407–1411
Mercken M, Vandermeeren M, Lübke U, Six J, Boons J, Van de Voorde A, Martin JJ, Gheuens J (1992) Monoclonal antibodies with selective specificity for Alzheimer Tau are directed against phosphatase-sensitive epitopes. Acta Neuropathol 84:265–272
Modrowski D, Lomri A, Marie PJ (1998) Glycosaminoglycans bind granulocyte–macrophage colony-stimulating factor and modulate its mitogenic activity and signaling in human osteoblastic cells. J Cell Physiol 177:187–195
Murer MG, Boissiere F, Yan Q, Hunot S, Villares J, Faucheux B, Agid Y, Hirsch E, Raisman-Vozari R (1999) An immunohistochemical study of the distribution of brain-derived neurotrophic factor in the adult human brain, with particular reference to Alzheimer’s disease. Neuroscience 88:1015–1032
Nataf S, Strazielle N, Hatterer E, Mouchiroud G, Belin MF, Ghersi-Egea JF (2006) Rat choroid plexuses contain myeloid progenitors capable of differentiation toward macrophage or dendritic cell phenotypes. Glia 54:160–171
Nitta T, Sato K, Allegretta M, Brocke S, Lim M, Mitchell DJ, Steinman L (1992) Expression of granulocyte colony stimulating factor and granulocyte–macrophage colony stimulating factor genes in human astrocytoma cell lines and glioma specimens. Brain Res 571:19–25
Perry G (1993) Neuritic plaques in Alzheimer’s disease originate from neurofibrillary tangles. Med Hypotheses 40:257–258
Perry G, Siedlak SL, Richey P, Kawai M, Cras P, Kalaria RN, Galloway PG, Scardina JM, Cordell B, Greenberg BD, Ledbetter SR, Gambetti P (1991) Association of heparan sulfate proteoglycan with the neurofibrillary tangles of Alzheimer’s disease. J Neurosci 11:3679–3683
Reed JA, Clegg DJ, Smith KB, Tolod-Richer EG, Matter EK, Picard LS, Seeley RJ (2005) GM-CSF action in the CNS decreases food intake and body weight. J Clin Invest 115:3035–3044
Sawada M, Itho Y, Suzumura A, Marunouchi T (1993) Expression of cytokine receptors in cultured neuronal and glial cells. Neurosci Lett 160:131–134
Schäbitz W-R, Krüger C, Pitzer C, Weber D, Laage R, Gassler N, Aronowski J, Mier W, Kirsch F, Dittgen T, Bach A, Sommer C, Schneider A (2008) A neuroprotective function for the hematopoietic protein granulocyte–macrophage colony stimulating factor (GM-CSF). J Cereb Blood Flow Metab 28:29–43
Schneeloch E, Mies G, Busch H-J, Buschmann IR, Hossmann K-A (2004) Granulocyte–macrophage colony-stimulating factor-induced arteriogenesis reduces energy failure in hemodynamic stroke. Proc Natl Acad Sci USA 101:12730–12735
Schneider UC, Schilling L, Schroeck H, Nebe T, Vajkoczy P, Woitzik J (2007) Granulocyte–macrophage colony-stimulating factor-induced vessel growth restores cerebral blood supply after bilateral carotid artery occlusion. Stroke 38:1320–1328
Siegel GJ, Chauhan NB (2000) Neurotrophic factors in Alzheimer’s and Parkinson’s disease brain. Brain Res Rev 33:199–227
Todo K, Kitagawa K, Sasaki T, Omura-Matsuoka E, Terasaki Y, Oyama N, Yagita Y, Hori M (2008) Granulocyte–macrophage colony-stimulating factor enhances leptomeningeal collateral growth induced by common carotid artery occlusion. Stroke 39:1875–1882
Tsai K-J, Tsai Y-C, Shen C-KJ (2007) G-CSF rescues the memory impairment of animal models of Alzheimer’s disease. J Exp Med 204:1273–1280
Yamaguchi H, Nakazato Y, Shoji M, Okamoto K, Ihara Y, Morimatsu M, Hirai S (1991) Secondary deposition of beta amyloid within extracellular neurofibrillary tangles in Alzheimer-type dementia. Am J Pathol 138:699–705
Acknowledgments
The authors kindly acknowledge the excellent technical support by Ralf Luderschmidt and Magdeleine Herkt. Furthermore, the authors would like to thank Astrid Wöber for superb editorial assistance. This work contains parts of the thesis of Sami Ridwan.
Conflict of interest
CJS is an inventor on the patent application “Hematopoietic factors for treatment of neurological conditions”. Recently a part of the application (ALS) was granted.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ridwan, S., Bauer, H., Frauenknecht, K. et al. Distribution of granulocyte–monocyte colony-stimulating factor and its receptor α-subunit in the adult human brain with specific reference to Alzheimer’s disease. J Neural Transm 119, 1389–1406 (2012). https://doi.org/10.1007/s00702-012-0794-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-012-0794-y