The Amyloid-beta rich CNS environment alters myeloid cell functionality independent of their origin.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
28 04 2020
28 04 2020
Historique:
received:
04
06
2018
accepted:
02
04
2020
entrez:
30
4
2020
pubmed:
30
4
2020
medline:
7
1
2021
Statut:
epublish
Résumé
Microglia, the innate immune cells of the central nervous system (CNS) survey their surroundings with their cytoplasmic processes, phagocytose debris and rapidly respond to injury. These functions are affected by the presence of beta-Amyloid (Aβ) deposits, hallmark lesions of Alzheimer's disease (AD). We recently demonstrated that exchanging functionally altered endogenous microglia with peripheral myeloid cells did not change Aβ-burden in a mouse model mimicking aspects of AD at baseline, and only mildly reduced Aβ plaques upon stimulation. To better characterize these different myeloid cell populations, we used long-term in vivo 2-photon microscopy to compare morphology and basic functional parameters of brain populating peripherally-derived myeloid cells and endogenous microglia. While peripherally-derived myeloid cells exhibited increased process movement in the non-diseased brain, the Aβ rich environment in an AD-like mouse model, which induced an alteration of surveillance functions in endogenous microglia, also restricted functional characteristics and response to CNS injury of newly recruited peripherally-derived myeloid cells. Our data demonstrate that the Aβ rich brain environment alters the functional characteristics of endogenous microglia as well as newly recruited peripheral myeloid cells, which has implications for the role of myeloid cells in disease and the utilization of these cells in Alzheimer's disease therapy.
Identifiants
pubmed: 32346002
doi: 10.1038/s41598-020-63989-3
pii: 10.1038/s41598-020-63989-3
pmc: PMC7189379
doi:
Substances chimiques
Amyloid beta-Peptides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7152Références
Querfurth, H. W. & LaFerla, F. M. Alzheimer’s Disease. New England Journal of Medicine 362, 329–344, https://doi.org/10.1056/NEJMra0909142 (2010).
doi: 10.1056/NEJMra0909142
pubmed: 20107219
Holtzman, D. M., Morris, J. C. & Goate, A. M. Alzheimer’s Disease: The Challenge of the Second Century. Science Translational Medicine 3, 77sr71–77sr71, https://doi.org/10.1126/scitranslmed.3002369 (2011).
doi: 10.1126/scitranslmed.3002369
Montine, T. J. et al. National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathologica 123, 1–11, https://doi.org/10.1007/s00401-011-0910-3 (2012).
doi: 10.1007/s00401-011-0910-3
pubmed: 22101365
Yeh, F. L., Hansen, D. V. & Sheng, M. TREM2, Microglia, and Neurodegenerative Diseases. Trends in Molecular Medicine 23, 512–533, https://doi.org/10.1016/j.molmed.2017.03.008 (2017).
doi: 10.1016/j.molmed.2017.03.008
pubmed: 28442216
Heppner, F. L., Ransohoff, R. M. & Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16, 358–372, https://doi.org/10.1038/nrn3880 (2015).
doi: 10.1038/nrn3880
pubmed: 25991443
Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo. Science 308, 1314–1318, https://doi.org/10.1126/science.1110647 (2005).
doi: 10.1126/science.1110647
pubmed: 15831717
Füger, P. et al. Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nature Neuroscience 20, 1371, https://doi.org/10.1038/nn.4631 , https://www.nature.com/articles/nn.4631#supplementary-information (2017).
Hefendehl, J. K. et al. Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell 13, 60–69, https://doi.org/10.1111/acel.12149 (2014).
doi: 10.1111/acel.12149
pubmed: 23953759
Krabbe, G. et al. Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology. PLoS ONE 8, e60921, https://doi.org/10.1371/journal.pone.0060921 (2013).
doi: 10.1371/journal.pone.0060921
pubmed: 23577177
pmcid: 3620049
vom Berg, J. et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease–like pathology and cognitive decline. Nature Medicine 18, 1812, https://doi.org/10.1038/nm.2965 , https://www.nature.com/articles/nm.2965#supplementary-information (2012).
Heneka, M. T. et al. NLRP3 is activated in Alzheimer/‘s disease and contributes to pathology in APP/PS1 mice. Nature advance online publication, http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature11729.html#supplementary-information (2012).
Lee, S. et al. CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer’s Disease Mouse Models. The American Journal of Pathology 177, 2549-2562, https://doi.org/10.2353/ajpath.2010.100265 .
Liu, Z., Condello, C., Schain, A., Harb, R. & Grutzendler, J. CX3CR1 in Microglia Regulates Brain Amyloid Deposition through Selective Protofibrillar Amyloid-β Phagocytosis. The Journal of Neuroscience 30, 17091–17101, https://doi.org/10.1523/jneurosci.4403-10.2010 (2010).
doi: 10.1523/jneurosci.4403-10.2010
pubmed: 21159979
pmcid: 3077120
Cho, S.-H. et al. CX3CR1 Protein Signaling Modulates Microglial Activation and Protects against Plaque-independent Cognitive Deficits in a Mouse Model of Alzheimer Disease. Journal of Biological Chemistry 286, 32713–32722, https://doi.org/10.1074/jbc.M111.254268 (2011).
doi: 10.1074/jbc.M111.254268
pubmed: 21771791
Chakrabarty, P. et al. Massive gliosis induced by interleukin-6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. The FASEB Journal 24, 548–559, https://doi.org/10.1096/fj.09-141754 (2010).
doi: 10.1096/fj.09-141754
pubmed: 19825975
pmcid: 3083918
Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481, https://doi.org/10.1038/nature21029, https://www.nature.com/articles/nature21029#supplementary-information (2017).
Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science, https://doi.org/10.1126/science.aad8373 (2016).
doi: 10.1126/science.aad8373
pubmed: 27701111
pmcid: 5094372
Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. V. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10, 1538–1543, http://www.nature.com/neuro/journal/v10/n12/suppinfo/nn2014_S1.html (2007).
Mildner, A. et al. Distinct and Non-Redundant Roles of Microglia and Myeloid Subsets in Mouse Models of Alzheimer’s Disease. The Journal of Neuroscience 31, 11159–11171, https://doi.org/10.1523/jneurosci.6209-10.2011 (2011).
doi: 10.1523/jneurosci.6209-10.2011
pubmed: 21813677
pmcid: 6623351
Stalder, A. K. et al. Invasion of Hematopoietic Cells into the Brain of Amyloid Precursor Protein Transgenic Mice. The Journal of Neuroscience 25, 11125–11132, https://doi.org/10.1523/jneurosci.2545-05.2005 (2005).
doi: 10.1523/jneurosci.2545-05.2005
pubmed: 16319312
pmcid: 6725647
Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. The Journal of Experimental Medicine 213, 667–675, https://doi.org/10.1084/jem.20151948 (2016).
doi: 10.1084/jem.20151948
pubmed: 27091843
pmcid: 4854736
Reed-Geaghan, E. G., Croxford, A. L., Becher, B. & Landreth, G. E. Plaque-associated myeloid cells derive from resident microglia in an Alzheimer’s disease model. The Journal of Experimental Medicine 217, https://doi.org/10.1084/jem.20191374 (2020).
Town, T. et al. Blocking TGF-β–Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nature Medicine 14, 681, https://doi.org/10.1038/nm1781 , https://www.nature.com/articles/nm1781#supplementary-information (2008).
Heppner, F. L. et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11, 146-152, http://www.nature.com/nm/journal/v11/n2/suppinfo/nm1177_S1.html (2005).
Prokop, S. et al. Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice. The Journal of Experimental Medicine 212, 1811–1818, https://doi.org/10.1084/jem.20150479 (2015).
doi: 10.1084/jem.20150479
pubmed: 26458768
pmcid: 4612091
Varvel, N. H. et al. Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer’s disease. The Journal of Experimental Medicine 212, 1803–1809, https://doi.org/10.1084/jem.20150478 (2015).
doi: 10.1084/jem.20150478
pubmed: 26458770
pmcid: 4612086
Luche, H., Weber, O., Nageswara Rao, T., Blum, C. & Fehling, H. J. Faithful activation of an extra-bright red fluorescent protein in “knock-in” Cre-reporter mice ideally suited for lineage tracing studies. European Journal of Immunology 37, 43–53, https://doi.org/10.1002/eji.200636745 (2007).
doi: 10.1002/eji.200636745
pubmed: 17171761
Grathwohl, S. A. et al. Formation and maintenance of Alzheimer’s disease [beta]-amyloid plaques in the absence of microglia. Nat Neurosci 12, 1361–1363, http://www.nature.com/neuro/journal/v12/n11/suppinfo/nn.2432_S1.html (2009).
Hefendehl, J. K. et al. Repeatable target localization for long-term in vivo imaging of mice with 2-photon microscopy. Journal of Neuroscience Methods 205, 357–363, https://doi.org/10.1016/j.jneumeth.2011.10.029 (2012).
doi: 10.1016/j.jneumeth.2011.10.029
pubmed: 22093765
Hefendehl, J. K. et al. Long-Term In Vivo Imaging of β-Amyloid Plaque Appearance and Growth in a Mouse Model of Cerebral β-Amyloidosis. The Journal of Neuroscience 31, 624–629, https://doi.org/10.1523/jneurosci.5147-10.2011 (2011).
doi: 10.1523/jneurosci.5147-10.2011
pubmed: 21228171
pmcid: 6623424
Mildner, A. et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nature Neuroscience 10, 1544, https://doi.org/10.1038/nn2015 , https://www.nature.com/articles/nn2015#supplementary-information (2007).
Varvel, N. H. et al. Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proceedings of the National Academy of Sciences 109, 18150-18155, https://doi.org/10.1073/pnas.1210150109 (2012).
Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M. & Rossi, F. M. V. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nature Neuroscience 14, 1142, https://doi.org/10.1038/nn.2887 , https://www.nature.com/articles/nn.2887#supplementary-information (2011).
Radde, R. et al. Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Reports 7, 940–946, https://doi.org/10.1038/sj.embor.7400784 (2006).
doi: 10.1038/sj.embor.7400784
pubmed: 16906128
pmcid: 1559665
Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8, 752–758, http://www.nature.com/neuro/journal/v8/n6/suppinfo/nn1472_S1.html (2005).
Prokop, S., Miller, K. R. & Heppner, F. L. Microglia actions in Alzheimer’s disease. Acta Neuropathologica 126, 461–477, https://doi.org/10.1007/s00401-013-1182-x (2013).
doi: 10.1007/s00401-013-1182-x
pubmed: 24224195
Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology. Brain 139, 1265–1281, https://doi.org/10.1093/brain/aww016 (2016).
doi: 10.1093/brain/aww016
pubmed: 26921617
pmcid: 5006229
Jay, T. R. et al. Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer’s Disease. The Journal of Neuroscience 37, 637–647, https://doi.org/10.1523/jneurosci.2110-16.2016 (2017).
doi: 10.1523/jneurosci.2110-16.2016
pubmed: 28100745
pmcid: 5242410
Yuan, P. et al. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron 90, 724–739, https://doi.org/10.1016/j.neuron.2016.05.003 (2016).
doi: 10.1016/j.neuron.2016.05.003
pubmed: 27196974
pmcid: 4898967
Keren-Shaul, H. et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell 169, 1276–1290.e1217, https://doi.org/10.1016/j.cell.2017.05.018 (2017).
doi: 10.1016/j.cell.2017.05.018
Krasemann, S. et al. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity 47, 566–581.e569, https://doi.org/10.1016/j.immuni.2017.08.008 (2017).
doi: 10.1016/j.immuni.2017.08.008
pubmed: 28930663
pmcid: 5719893
Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. The Journal of Experimental Medicine 212, 287–295, https://doi.org/10.1084/jem.20142322 (2015).
doi: 10.1084/jem.20142322
pubmed: 25732305
pmcid: 4354365
Derecki, N. C. et al. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484, 105, https://doi.org/10.1038/nature10907 , https://www.nature.com/articles/nature10907#supplementary-information (2012).
Cronk, J. C. et al. Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. The Journal of Experimental Medicine, https://doi.org/10.1084/jem.20180247 (2018).
Han, K. H., Arlian, B. M., Macauley, M. S., Paulson, J. C. & Lerner, R. A. Migration-based selections of antibodies that convert bone marrow into trafficking microglia-like cells that reduce brain amyloid β. Proceedings of the National Academy of Sciences, https://doi.org/10.1073/pnas.1719259115 (2018).
De Strooper, B. & Karran, E. The Cellular Phase of Alzheimer’s Disease. Cell 164, 603–615, https://doi.org/10.1016/j.cell.2015.12.056 (2016).
doi: 10.1016/j.cell.2015.12.056
Jung, S. et al. Analysis of Fractalkine Receptor CX(3)CR1 Function by Targeted Deletion and Green Fluorescent Protein Reporter Gene Insertion. Molecular and Cellular Biology 20, 4106–4114 (2000).
doi: 10.1128/MCB.20.11.4106-4114.2000
Herz, J. et al. Expanding Two-Photon Intravital Microscopy to the Infrared by Means of Optical Parametric Oscillator. Biophysical Journal 98, 715–723, https://doi.org/10.1016/j.bpj.2009.10.035 (2010).
doi: 10.1016/j.bpj.2009.10.035
pubmed: 20159168
pmcid: 2820639
Klunk, W. E. et al. Imaging Aβ Plaques in Living Transgenic Mice with Multiphoton Microscopy and Methoxy-X04, a Systemically Administered Congo Red Derivative. Journal of Neuropathology & Experimental Neurology 61, 797–805, https://doi.org/10.1093/jnen/61.9.797 (2002).
Parslow, A., Cardona, A. & Bryson-Richardson, R. J. Sample Drift Correction Following 4D Confocal Time-lapse Imaging. e51086, https://doi.org/10.3791/51086 (2014).