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Microglial Cell Dysregulation in the Aged Brain and Neurodegeneration

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Abstract

For several decades, microglia were considered to be subordinated to neurons. However, growing evidence indicates that microglia play key roles in the normal functioning of the nervous system, as well as in age-dependent changes and neurodegenerative diseases. As the brain ages, microglia acquire a phenotype that can be increasingly inflammatory and cytotoxic (dysfunctional microglia), generating a hostile environment for neurons. There is mounting evidence that this process facilitates the development of neurodegenerative diseases, for which the greatest risk factor is age. In neurodegenerative diseases, the abnormal inflammatory response can depend on the impairment of the endogenous activation control of aging microglia that potentiate the release of potentially detrimental factors such as cytokines and oxidative stress mediators. This chapter will discuss key aging-dependent changes occurring in microglia, the inflammatory and oxidative environment they establish, their impaired regulation, and their interaction and effect on neurons. In addition, the role of complement in the neuron-microglia interaction and their modeling of neural circuits through microglia-mediated phagocytosis in development will be highlighted, as well as the growing evidence on its contribution in neurodegenerative processes.

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Abbreviations

ATP:

Adenosine triphosphate

bFGF:

Basic fibroblast growth factor

C3a:

Anaphylatoxin originating from activation and cleavage of complement component 3

C3b:

By-products of the classical pathway of complement activation (C3)

C3d:

Breakdown products of C3b

C5a:

Anaphylatoxin originating from activation and cleavage of complement 5

C5b:

By-products of the classical pathway of complement activation (C5)

CNS:

Central nervous system

CR3; CD11b/CD18:

Complement receptor 3

CX3CL1:

CX3C chemokine subclass (fractalkine)

CX3CR1:

Fractalkine receptor

IFNγ:

Interferon gamma

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

IL-10:

Interleukin-10

LPS:

Lipopolysaccharides

MHC II:

Class II molecules of major histocompatibility complex

NGF:

Nerve growth factor

NMDA:

N-Methyl-D-aspartate

NO:

Nitric oxide

TGFβ:

Transforming growth factor β

TNFα:

Tumor necrosis factor α

TREM2:

Triggering receptor expressed on myeloid cells 2

References

  • Beltrán-Castillo, S., Eugenín, J., & von Bernhardi, R. (2018) Impact of aging in microglia mediated D-serine balance in the CNS. Mediators of Inflammation, 7219732. https://doi.org/10.1155/2018/7219732

  • Benoit, M. E., & Tenner, A. J. (2011). Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and microRNA expression. The Journal of Neuroscience, 31, 3459–3469.

    Article  CAS  Google Scholar 

  • Bialas, A., & Stevens, B. (2013). TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nature Neuroscience, 16, 1773–1782. https://doi.org/10.1038/nn.3560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biber, K., de Jong, E. K., van Weering, H. R. J., & Boddeke, H. W. (2006). Chemokines and their receptors in central nervous system disease. Current Drug Targets, 7, 29. https://doi.org/10.2174/138945006775270196

    Article  CAS  PubMed  Google Scholar 

  • Biber, K., Neumann, H., Inoue, K., & Boddeke, H. W. (2007). Neuronal ‘On’ and ‘Off’ signals control microglia. Trends in Neurosciences, 30(11), 596–602. https://doi.org/10.1016/j.tins.2007.08.007

    Article  CAS  PubMed  Google Scholar 

  • Bruttger, J., Karram, K., Wörtge, S., Regen, T., Marini, F., Hoppmann, N., Klein, M., Blank, T., Yona, S., Wolf, Y., Mack, M., Pinteaux, E., Müller, W., Zipp, F., Binder, H., Bopp, T., Prinz, M., Jung, S., & Waisman, A. (2015). Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity, 43(1), 92–106. https://doi.org/10.1016/j.immuni.2015.06.012

    Article  CAS  PubMed  Google Scholar 

  • Chekeni, F. B., Elliott, M. R., Sandilos, J. K., Walk, S. F., Kinchen, J. M., Lazarowski, E. R., Armstrong, A. J., Penuela, S., Laird, D. W., Salvesen, G. S., Isakson, B. E., Bayliss, D. A., & Ravichandran, K. S. (2010). Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature, 467(7317), 863–867.

    Article  CAS  Google Scholar 

  • Cherry, J. D., Olschowka, J. A., & O’Banion, M. K. (2014). Neuroinflammation and M2 microglia: The good, the bad, and the inflamed. Journal of Neuroinflammation, 11, 98. https://doi.org/10.1186/1742-2094-11-98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cornejo, F., Vruwink, M., Metz, C., Muñoz, P., Salgado, N., Poblete, J., Andrés, M. E., & von Bernhardi, R. (2018). SR-A deficiency impairs immune response of microglia and astrocytes potentiating Alzheimer’s disease pathophysiology. Brain, Behavior, and Immunity, 69, 336–350. https://doi.org/10.1016/j.bbi.2017.12.007

    Article  CAS  PubMed  Google Scholar 

  • Crews, F. T., Zou, J., & Coleman Jr., L. G. (2021). Extracellular microvesicles promote microglia-mediated pro-inflammatory responses to ethanol. Journal of Neuroscience Research, n/a. https://doi.org/10.1002/jnr.24813.

  • Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W. B. (2005). ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience, 8, 752–758.

    Article  CAS  Google Scholar 

  • Dissing-Olesen, L., LeDue, J. M., Rungta, R. L., Hefendehl, J. K., Choi, H. B., & MacVicar, B. A. (2014). Activation of neuronal NMDA receptors triggers transient ATP-mediated microglial process outgrowth. The Journal of Neuroscience, 34, 10511–10527.

    Article  Google Scholar 

  • Elliott, M. R., Chekeni, F. B., Trampont, P. C., Lazarowski, E. R., Kadl, A., Walk, S. F., Park, D., Woodson, R. I., Ostankovich, M., Sharma, P., Lysiak, J. J., Harden, T. K., Leitinger, N., & Ravichandran, K. S. (2009). Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature, 461(7261), 282–286.

    Article  CAS  Google Scholar 

  • Eyüpoglu, L. Y., Bechmann, L., & Nitsch, R. (2003). Modification of microglial function protects from lesion-induced neuronal alteration and promotes sprouting in the hippocampus. The FASEB Journal, 17, 1110–1111.

    Article  Google Scholar 

  • Frank, M. G., Barrientos, R. M., Biedenkapp, J. C., Rudy, J. W., Watkins, L. R., & Maier, S. F. (2006). mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiology of Aging, 27, 717–722.

    Article  CAS  Google Scholar 

  • Frank, M. G., Baratta, M. V., Sprunger, D. B., Watkins, L. R., & Maier, S. F. (2007). Microglia serve as a neuroimmune substrate for stress induced potentiation of CNS pro-inflammatory cytokine responses. Brain, Behavior, and Immunity, 21, 47–59.

    Article  CAS  Google Scholar 

  • Godbout, J. P., Chen, J., Abraham, J., Richwine, A. F., Berg, B. M., Kelley, K. W., & Johnson, R. W. (2005). Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. The FASEB Journal, 19, 1329–1331.

    Article  CAS  Google Scholar 

  • Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S., Younkin, S., Hazrati, L., Collinge, J., Pocock, J., Lashley, T., Williams, J., Lambert, J. C., Amouyel, P., Goate, A., Rademakers, R., … Hardy, J. (2013). Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer’s disease. The New England Journal of Medicine, 368(2), 117–127. https://doi.org/10.1056/NEJMoa1211851

    Article  CAS  PubMed  Google Scholar 

  • Hakobyan, S., Harding, K., Aiyaz, M., Hye, A., Dobson, R., Baird, A., Liu, B., Harris, C. L., Lovestone, S., & Morgan, B. P. (2016). Complement biomarkers as predictors of disease progression in Alzheimer’s disease. Journal of Alzheimer’s Disease, 54(2), 707–716. https://doi.org/10.3233/JAD-160420

    Article  CAS  PubMed  Google Scholar 

  • Hayashi, Y., Yoshida, M., Yamato, M., Ide, T., Wu, Z., Ochi-Shindou, M., Kanki, T., Kang, D., Sunagawa, K., Tsutsui, H., & Nakanishi, H. (2008). Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice. The Journal of Neuroscience, 28, 8624–8634. https://doi.org/10.1523/jneurosci.1957-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haynes, S. E., Hollopeter, G., Yang, G., Kurpius, D., Dailey, M. E., Gan, W. B., & Julius, D. (2006). The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nature Neuroscience, 9(12), 1512–1519.

    Article  CAS  Google Scholar 

  • Hefendehl, J. K., Neher, J. J., Sühs, R. B., Kohsaka, S., Skodras, A., & Jucker, M. (2014). Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell, 13(1), 60–69. https://doi.org/10.1111/acel.12149

    Article  CAS  PubMed  Google Scholar 

  • Henry, C. J., Huang, Y., Wynne, A. M., & Godbout, J. P. (2009). Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain, Behavior, and Immunity, 23, 309–317.

    Article  CAS  Google Scholar 

  • Holmes, C., Cunningham, C., Zotova, E., Woolford, J., Dean, C., Kerr, S., Culliford, D., & Perry, V. H. (2009). Systemic inflammation and disease progression in Alzheimer disease. Neurology, 73(10), 768–774.

    Article  CAS  Google Scholar 

  • Huang, Y., Xu, Z., Xiong, S., Sun, F., Qin, G., Hu, G., Wang, J., Zhao, L., Liang, Y., Wu, T., Lu, Z., Humayun, S. M., So, K. F., Pan, Y., Li, N., Yuan, T. F., Rao, Y., & Peng, B. (2018). Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion. Nature Neuroscience, 21, 530–540. https://doi.org/10.1038/s41593-018-0090-8

    Article  CAS  PubMed  Google Scholar 

  • Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., Rujescu, D., Hampel, H., Giegling, I., Andreassen, O. A., Engedal, K., Ulstein, I., Djurovic, S., Ibrahim-Verbaas, C., Hofman, A., … Stefansson, K. (2013). Variant of TREM2 associated with the risk of Alzheimer’s disease. New England Journal of Medicine, 368(2), 107–116. https://doi.org/10.1056/NEJMoa1211103

    Article  CAS  Google Scholar 

  • Li, Y., Du, X. F., Liu, C. S., Wen, Z. L., & Du, J. L. (2012). Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Developmental Cell, 23, 1189–1202.

    Article  CAS  Google Scholar 

  • Li, Q., Cheng, Z., Zhou, L., Darmanis, S., Neff, N. F., Okamoto, J., Gulati, G., Bennett, M. L., Sun, L. O., Clarke, L. E., Marschallinger, J., Yu, G., Quake, S. R., Wyss-Coray, T., & Barres, B. A. (2019). Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron, 101(2), 207–223.e10. https://doi.org/10.1016/j.neuron.2018.12.006

  • Maggi, L., Scianni, M., Branchi, I., D’Andrea, I., Lauro, C., & Limatola, C. (2011). CX3CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment. Frontiers in Cellular Neuroscience, 5, 22.

    Article  CAS  Google Scholar 

  • Marín-Teva, J. L., Dusart, L., Colin, C., Gervais, A., van Rooijen, N., & Mallat, M. (2004). Microglia promote the death of developing Purkinje cells. Neuron, 41(4), 535–547. https://doi.org/10.1016/S0896-6273(04)00069-8

    Article  PubMed  Google Scholar 

  • Moriyama, M., Fukuhara, T., Britschgi, M., Yingbo, H., Narasimhan, R., Villeda, S., Molina, H., Huber, B. T., Holers, M., & Wyss-Coray, T. (2011). Complement receptor 2 is expressed in neural progenitor cells and regulates adult hippocampal neurogenesis. Journal of Neuroscience, 31(11), 3981–3989.

    Article  CAS  Google Scholar 

  • Nair, S., Sobotka, K. S., Joshi, P., Gressens, P., Fleiss, B., Thornton, C., Mallard, C., & Hagberg, H. (2019). Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo. Glia, 67, 1047–1061. https://doi.org/10.1002/glia.23587

    Article  PubMed  Google Scholar 

  • Nguyen, P. T., Dorman, L. C., Pan, S., Vainchtein, I. D., Han, R. T., Nakao-Inoue, H., Taloma, S. E., Barron, J. J., Molofsky, A. B., Kheirbek, M. A., & Molofsky, A. V. (2020). Microglial remodeling of the extracellular matrix promotes synapse plasticity. Cell, 182(2), 388–403. https://doi.org/10.1016/j.cell.2020.05.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 308, 1314–1318.

    Article  CAS  Google Scholar 

  • Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto, M., Ferreira, T. A., Guiducci, E., Dumas, L., Ragozzino, D., & Gross, C. T. (2011). Synaptic pruning by microglia is necessary for normal brain development. Science, 333(6048), 1456–1458. https://doi.org/10.1126/science.1202529

    Article  CAS  PubMed  Google Scholar 

  • Parkhurst, C. N., Yang, G., Ninan, I., Savas, J. N., Yates, J. R., Lafaille, J. J., Hempstead, B. L., Littman, D. R., & Gan, W. B. (2013). Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell, 155, 1596–1609.

    Article  CAS  Google Scholar 

  • Pawate, S., Shen, Q., Fan, F., & Bhat, N. R. (2004). Redox regulation of glial inflammatory response to lipopolysaccharide and interferon gamma. Journal of Neuroscience Research, 77, 540–551. https://doi.org/10.1002/jnr.20180

    Article  CAS  PubMed  Google Scholar 

  • Peterson, S. L., Nguyen, H. X., & Mendez, O. A. (2017). Complement protein C3 suppresses axon growth and promotes neuron loss. Scientific Reports, 7, 12904. https://doi.org/10.1038/s41598-017-11410-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qin, L., Li, G., Qian, X., Liu, Y., Wu, X., Liu, B., Hong, J. S., & Block, M. L. (2005). Interactive role of the toll-like receptor 4 and reactive oxygen species in LPS-induced microglia activation. Glia, 52, 78–84. https://doi.org/10.1002/glia.20225

    Article  PubMed  Google Scholar 

  • Rahpeymai, Y., Hietala, M. A., Wilhelmsson, U., Fotheringham, A., Davies, I., Nilsson, A. K., Zwirner, J., Wetsel, R. A., Gerard, C., Pekny, M., & Pekna, M. (2006). Complement: A novel factor in basal and ischemia-induced neurogenesis. The EMBO Journal, 25(6), 1364–1374.

    Article  CAS  Google Scholar 

  • Rogers, J. T., Morganti, J. M., Bachstetter, A. D., Hudson, C. E., Peters, M. M., Grimmig, B. A., Weeber, E. J., Bickford, P. C., & Gemma, C. (2011). CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. The Journal of Neuroscience, 31, 16241–16250.

    Article  CAS  Google Scholar 

  • Ruqayya, A., Jong-Heon, K., Habibur, R., & Kyoungho, S. (2020). Metabolic regulation of glial phenotypes: Implications in neuron–glia interactions and neurological disorders. Frontiers in Cellular Neuroscience, 14, 20. https://doi.org/10.3389/fncel.2020.00020

    Article  CAS  Google Scholar 

  • Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012). Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron, 74, 691–705. https://doi.org/10.1016/j.neuron.2012.03.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sierra, A., Gottfried-Blackmorem, A. C., McEwen, B. S., & Bulloch, K. (2007). Microglia derived from aging mice exhibit an altered inflammatory profile. Glia, 55, 412–424.

    Article  Google Scholar 

  • Simon, E., Obst, J., & Gomez-Nicola, D. (2019). The evolving dialogue of microglia and neurons in Alzheimer’s disease: Microglia as necessary transducers of pathology. Neuroscience, 405, 24–34. https://doi.org/10.1016/j.neuroscience.2018.01.059

    Article  CAS  PubMed  Google Scholar 

  • Stephan, A. H., Madison, D. V., Mateos, J. M., Fraser, D. A., Lovelett, E. A., Coutellier, L., Kim, L., Tsai, H. H., Huang, E. J., Rowitch, D. H., Berns, D. S., Tenner, A. J., Shamloo, M., & Barres, B. A. (2013). A dramatic increase of C1q protein in the CNS during normal aging. The Journal of Neuroscience, 33, 13460–13474. https://doi.org/10.1523/JNEUROSCI.1333-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., Micheva, K. D., Mehalow, A. K., Huberman, A. D., Stafford, B., Sher, A., Litke, A. M., Lambris, J. D., Smith, S. J., John, S. W., & Barres, B. A. (2007). The classical complement cascade mediates CNS synapse elimination. Cell, 131(6), 1164–1178.

    Article  CAS  Google Scholar 

  • Subhramanyam, C. S., Wang, C., Hu, Q., & Dheen, S. T. (2019). Microglia-mediated neuroinflammation in neurodegenerative diseases. Seminars in Cell & Developmental Biology, 94, 112–120. https://doi.org/10.1016/j.semcdb.2019.05.004

    Article  CAS  Google Scholar 

  • Tremblay, M. È., Lowerym, R. L., & Majewska, A. K. (2010). Microglial interactions with synapses are modulated by visual experience. PLoS Biology, 8(11), e1000527. https://doi.org/10.1371/journal.pbio.1000527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ueno, M., Fujita, Y., Tanaka, T., Nakamura, Y., Kikuta, J., Ishii, M., & Yamashita, T. (2013). Layer V cortical neurons require microglial support for survival during postnatal development. Nature Neuroscience, 16(5), 543–551.

    Article  CAS  Google Scholar 

  • Vainchtein, I. D., & Molofsky, A. V. (2020). Astrocytes and microglia: In sickness and in health. Trends in Neurosciences, 43(3), 144–154.

    Article  CAS  Google Scholar 

  • Verge, G. M., Milligan, E. D., Maier, S. F., Watkins, L. R., Naeve, G. S., & Foster, A. C. (2004). Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. European Journal of Neuroscience, 20(5), 1150–1160. https://doi.org/10.1111/j.1460-9568.2004.03593.x

    Article  Google Scholar 

  • von Bernhardi, R., Ramírez, G., Toro, R., & Eugenín, J. (2007). Pro-inflammatory conditions promote neuronal damage mediated by amyloid precursor protein-and degradation by microglial cells in culture. Neurobiology of Disease, 26, 153–164.

    Article  Google Scholar 

  • von Bernhardi, R., Eugenin-von Bernhardi, L., & Eugenin, J. (2015). Microglial cell dysregulation in brain aging and neurodegeneration. Frontiers in Aging Neuroscience, 7, 124. https://doi.org/10.3389/fnagi.2015.00124

    Article  Google Scholar 

  • Zhan, Y., Paolicelli, R. C., Sforazzini, F., Weinhard, L., Bolasco, G., Pagani, F., Vyssotski, A. L., Bifone, A., Gozzi, A., Ragozzino, D., & Gross, C. T. (2014). Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nature Neuroscience, 17, 400–406.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge the support from the Agencia Nacional de Investigación y Desarrollo-Fondo Nacional de Desarrollo Científico y Tecnológico (ANID-FONDECYT) grant 1172647, ANID-REDES 190187, and Universia Santander to RvB.

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Authors and Affiliations

  1. Facultad de Ciencias de la Salud, Universidad San Sebastián, Santiago, Chile

    María Triolo-Mieses & Rommy von Bernhardi

  2. Facultad de Química y Biología, Departamento de Biología, Universidad de Santiago de Chile, Santiago, Chile

    María Triolo-Mieses

  3. Facultad de Medicina, Departamento de Neurología, Pontificia Universidad Católica de Chile, Santiago, Chile

    Ricardo Fadic & Rommy von Bernhardi

Authors
  1. María Triolo-Mieses
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  2. Ricardo Fadic
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  3. Rommy von Bernhardi
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Correspondence to Rommy von Bernhardi .

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  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Triolo-Mieses, M., Fadic, R., von Bernhardi, R. (2021). Microglial Cell Dysregulation in the Aged Brain and Neurodegeneration. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_180-1

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