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Astrocytes Regulate Microglial Phagocytosis of Senile Plaque Cores of Alzheimer's Disease
Abstract
We have developed an in vitro model in which isolated senile plaque (SP) cores are presented to rat microglial cells in culture. Microglia rapidly phagocytosed, broke apart, and cleared SP cores. However, when cocultured with astrocytes, microglial phagocytosis was markedly suppressed, allowing the SPs to persist. Suppression of phagocytosis by astrocytes appears to be a general phenomena since microglia in the presence of astrocytes showed reduced capacity to phagocytose latex beads as well. The astrocyte effect on microglia is related in part to a diffusible factor(s) since astrocyte- but not fibroblast-conditioned media also reduced phagocytosis. These results suggest that while microglia have the capacity to phagocytose and remove SPs, astrocytes which lie in close association to microglia may help prevent the efficient clearance of SP material allowing them to persist in Alzheimer's disease.
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“Moreover, astrocytes can also modulate microglial responses to Aβ [55, 58, 59].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [59]
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Amyloid-β and τ serve antioxidant functions in the aging and Alzheimer brain
Smith, M. A., Casadesús, G., Joseph, J. A., & Perry, G. L. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)01021-3 · Cited by 189
Self-citationCedernaes, J., Osorio, R. S., Varga, A. W., Kam, K., Schiöth, H. B., & Benedict, C. (2016) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2016.02.002 · Cited by 211
The innate immune system in demyelinating disease
Mayo, L., Quintana, F. J., & Weiner, H. L. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01135.x · Cited by 192
“By secreting GM-CSF, M-CSF, or TGF, the astrocytes may regulate MHC class II expression on microglial cells (172) and even regulate microglial phagocytosis (215).”
BackgroundAstrocyte-derived GDNF is a potent inhibitor of microglial activation
Rocha, S. M., Cristóvão, A. C., Campos, F. L., Fonseca, C. P., & Baltazar, G. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.04.014 · Cited by 189
Amyloid beta deregulates astroglial mGluR5‐mediated calcium signaling via calcineurin and Nf‐kB
Lim, D., Iyer, A., Ronco, V., Grolla, A. A., Canonico, P. L., Aronica, E., & Genazzani, A. A. (2013) · Glia · doi:10.1002/glia.22502 · Cited by 169
“Reactive astrocytes, present also in normal aging, are found in AD postmortem brains, as well as in animal models, around amyloid plaques (DeWitt et al., 1998).”
BackgroundPihlaja, R., Koıstınaho, J., Malm, T., Sikkilä, H., Vainio, S. J., & Koistinaho, M. (2007) · Glia · doi:10.1002/glia.20599 · Cited by 165
“…et al., 1998; Hu et al., 1998; Koistinaho and Koistinaho, 2002; Wallace et al., 1997), evidence exists that these cells are also involved in the clearance of Ab from the central nervous system (CNS) (DeWitt et al., 1998; Koistinaho et al., 2004; Matsunaga et al., 2003; Wyss-Coray et al., 2003).”
BackgroundInfluentialMechanisms of Neurodegeneration and Axonal Dysfunction in Progressive Multiple Sclerosis
Correale, J., Marrodan, M., & Ysrraelit, M. C. (2019) · Biomedicines · doi:10.3390/biomedicines7010014 · Cited by 167
“In addition, astrocytes can secrete GM-CSF, M-CSF or TGF-β, which can regulate MHC Class II molecule expression by microglia and even their phagocytosis [119].”
BackgroundAltered lymphocyte distribution in Alzheimer’s disease
RICHARTZSALZBURGER, E., BATRA, A., STRANSKY, E., LASKE, C., KOHLER, N., BARTELS, M., BUCHKREMER, G., & SCHOTT, K. (2007) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2006.01.010 · Cited by 167
Expression of Scavenger Receptors in Glial Cells
Alarcón, R., Fuenzalida, C., Santibáñez, M., & Rommy von Bernhardi, M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414686200 · Cited by 159
Yumoto, S., Kakimi, S., Ohsaki, A., & Ishikawa, A. (2009) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2009.07.023 · Cited by 166
Role of Neuroinflammation in Adult Neurogenesis and Alzheimer Disease: Therapeutic Approaches
Fuster-Matanzo, A., Llorens-Martı́n, M., Hernández, F., & Ávila, J. (2013) · Mediators of Inflammation · doi:10.1155/2013/260925 · Cited by 150
“Similarly, astrocytes might be activated by Aβ [76], contributing to generating a proinflammatory environment via the liberation of several cytokines and chemokines.”
Background“Targeting astrocytes in CNS injury and disease: A translational research approach”
Filous, A. R., & Silver, J. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.03.009 · Cited by 151
Self-citationRole of TGFβ signaling in the pathogenesis of Alzheimer’s disease
von Bernhardi, R., Cornejo, F., Parada, G. E., & Eugenín, J. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00426 · Cited by 149
“Microglial cell reactivity to Aβ and phagocytic activity are modulated by astrocytes, attenuating the cytotoxic response of microglia (DeWitt et al., 1998; von Bernhardi and Ramírez, 2001).”
BackgroundCollingwood, J. F., Chong, R. K. K., Kasama, T., Cervera-Gontard, L., Dunin-Borkowski, R. E., Perry, G., Pósfai, M., Siedlak, S. L., Simpson, E. T., Smith, M. A., et al. (2008) · Journal of Alzheimer's Disease · doi:10.3233/jad-2008-14211 · Cited by 147
“To map and identify iron compounds in isolated AD plaque core material, peptide cores and core fragments were purified from frozen cortical brain tissue as previously described [14], sourcing tissue from two pathologically confirmed cases of AD, aged 76 and 81 years.”
MethodSelf-citationAtwood, C., Martins, R. N., Smith, M. A., & Perry, G. L. (2002) · Peptides · doi:10.1016/s0196-9781(02)00070-0 · Cited by 142
Self-citationDiverse microglial motility behaviors during clearance of dead cells in hippocampal slices
Petersen, M. A., & Dailey, M. E. (2004) · Glia · doi:10.1002/glia.10362 · Cited by 139
“because other resident glia and neurons regulate microglial morphology, motility, and phagocytosis (Sievers et al., 1994; DeWitt et al., 1998; Smith and Hoerner, 2000; Chan et al., 2001; Hailer et al., 2001).”
BackgroundWilhelmus, M. M. M., de Waal, R. M. W., & Verbeek, M. M. (2007) · Molecular Neurobiology · doi:10.1007/s12035-007-0029-7 · Cited by 125
“fragments via phagocytosis [185–187].”
Neuroinflammation and anti-inflammatory therapy for Alzheimer’s disease
Moore, A. H., & O’Banion, M. K. (2002) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(02)00162-x · Cited by 150
Wilkinson, B. L., Koenigsknecht-Talboo, J., Grommes, C., Lee, C. Y. D., & Landreth, G. E. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600627200 · Cited by 131
Amyloid-β in Alzheimer Disease: The Null versus the Alternate Hypotheses
Lee, H., Zhu, X., Castellani, R. J., Nunomura, A., Perry, G. L., & Smith, M. A. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.114009 · Cited by 142
“This argues against the neurotoxic role of A in vivo, as does the observation that cultured neurons can be cultured directly on top of isolated A plaques or immobilizing A without any notable toxicity (Canning et al., 1993; Carpenter et al., 1993; DeWitt et al., 1998).”
BackgroundSelf-citationComplement Component C1q Modulates the Phagocytosis of Aβ by Microglia
Webster, S. D., Yang, A. J., Margol, L., Garzon-Rodriguez, W., Glabe, C. G., & Tenner, A. J. (2000) · Experimental Neurology · doi:10.1006/exnr.1999.7260 · Cited by 138
Glial cell dysregulation: a new perspective on Alzheimer disease
Rommy von Bernhardi, M. (2007) · Neurotoxicity Research · doi:10.1007/bf03033906 · Cited by 141
“Astrocytes affect the interaction of microglia with A , reducing microglial activation (von Bernhardi and Ramírez, 2001), altering their phagocytic capability (DeWitt et al., 1998) and attenuating the production of ROS and TNF- (Smits et al., 2001).”
BackgroundNeuropathology of Alzheimer disease: pathognomonic but not pathogenic
Castellani, R. J., Lee, H., Zhu, X., Nunomura, A., Perry, G. L., & Smith, M. A. (2006) · Acta Neuropathologica · doi:10.1007/s00401-006-0071-y · Cited by 133
“immobilized amyloid- elicit neurotoxity in vivo or in vitro [10, 17, 20] (Fig.”
BackgroundSelf-citationEskes, C., Honegger, P., Juillerat‐Jeanneret, L., & Monnet‐Tschudi, F. (2001) · Glia · doi:10.1002/glia.10019 · Cited by 122
YAZAWA, H., YU, Z.-X., TAKEDA, K., LE, Y., GONG, W., FERRANS, V. J., OPPENHEIM, J. J., LI, C. C. H., & WANG, J. M. (2001) · The FASEB Journal · doi:10.1096/fj.01-0251com · Cited by 105
Immunological regulation of neuronal degeneration and regeneration in the injured spinal cord
Popovich, P. G. (2000) · Progress in brain research · doi:10.1016/s0079-6123(00)28006-0 · Cited by 112
Phagocytic Clearance in Neurodegeneration
Sokolowski, J. D., & Mandell, J. W. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2010.12.051 · Cited by 120
“Nonetheless, the glial response to A in tissue isolated from AD brains appears to vary, and there have been conflicting reports as to whether astrocytes and microglia can clear A plaques ex vivo.(4,39,40) The relative roles of astrocytes and microglia in A clearance in vivo remain to be definitively clarified.”
BackgroundInfluentialEskes, C., Juillerat-Jeanneret, L., Leuba, G., Honegger, P., & Monnet-Tschudi, F. (2003) · Journal of Neuroscience Research · doi:10.1002/jnr.10508 · Cited by 114
“This observation is in agreement with a previous study showing that the presence of astrocytes decreased microglial reactivity (DeWitt et al., 1998).”
ResultIribarren, P., Zhou, Y., Hu, J., Le, Y., & Wang, J. M. (2005) · Immunologic Research · doi:10.1385/ir:31:3:165 · Cited by 108
“This was supported by studies of rat microglial cells (53–55) showing that Aβ42 taken by such cells could be degraded ( 56 ,57), and, as a consequence, these cells were capable of breaking apart phagocytosed AD plaque cores (56).”
ResultLewis, D. K., Johnson, A. B., Stohlgren, S., Harms, A. S., & Sohrabji, F. (2008) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2008.01.006 · Cited by 105
“Astrocytes have also been shown to suppress microglia phagocytosis (DeWitt et al., 1998) and astrocyte-derived transforming growth factor beta (TGFb)-1 is responsible for converting activated (phagocytic) microglia to resting microglia (Schilling et al.”
Copper and Alzheimer’s Disease
Mathys, Z. K., & White, A. R. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-60189-2_10 · Cited by 115
Gene expression profiling of scrapie-infected brain tissue
Riemer, C., Neidhold, S., Burwinkel, M., Schwarz, A., Schultz, J., Krätzschmar, J., Mönning, U., & Baier, M. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.08.124 · Cited by 108
Schilling, T., Nitsch, R., Heinemann, U., Haas, D., & Eder, C. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01661.x · Cited by 108
“It has also been reported that astrocytes are capable of suppressing microglial phagocytosis (DeWitt et al., 1998) as well as the production of the proin¯ammatory cytokine interleukin-12 (Aloisi et al., 1997).”
BackgroundAndersson, A. K., Rönnbäck, L., & Hansson, E. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03132.x · Cited by 108
Pharmacological approaches to mitigate neuroinflammation in Alzheimer’s disease
Uddin, M. S., Kabir, M. T., Mamun, A. A., Barreto, G. E., Rashid, M., Perveen, A., & Ashraf, G. M. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106479 · Cited by 121
Translational potential of astrocytes in brain disorders
Verkhratsky, A., Steardo, L., Parpura, V., & Montana, V. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.09.003 · Cited by 115
“Experiments in vitro documented reactive changes in cultured astrocytes after exposure to soluble β-amyloid (DeWitt et al., 1998); this reactivity was also associated with an abnormal Ca2+ oscillations (Abramov et al., 2003, 2004).”
BackgroundMechanisms of amyloid plaque pathogenesis
Fiala, J. C. (2007) · Acta Neuropathologica · doi:10.1007/s00401-007-0284-8 · Cited by 99
The Locus Coeruleus in Aging and Alzheimer’s Disease: A Postmortem and Brain Imaging Review
Beardmore, R., Hou, R. H., Darekar, A., Holmes, C., & Boche, D. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210191 · Cited by 132
Role of Interleukin-1 in Prion Disease-Associated Astrocyte Activation
Schultz, J., Schwarz, A., Neidhold, S., Burwinkel, M., Riemer, C., Simon, D., Köpf, M., Otto, M., & Baier, M. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63331-7 · Cited by 100
Liu, T., Perry, G. L., Chan, H. W., Verdile, G., Martins, R. N., Smith, M. A., & Atwood, C. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02196.x · Cited by 85
Self-citationAβ leads to Ca2+ signaling alterations and transcriptional changes in glial cells
Grolla, A. A., Fakhfouri, G., Balzaretti, G., Marcello, E. E., Gardoni, F., Canonico, P. L., Luca, M. D., Genazzani, A. A., & Lim, D. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.05.005 · Cited by 93
“, 2009) and strogliosis (DeWitt et al., 1998).”
Gallagher, J. J., Minogue, A. M., & Lynch, M. A. (2012) · Neurodegenerative Diseases · doi:10.1159/000337458 · Cited by 99
Afridi, R., Kim, J., Rahman, M. H., & Suk, K. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00020 · Cited by 102
Iribarren, P., Chen, K., Hu, J., Gong, W., Cho, E. H., Lockert, S., Uranchimeg, B., & Wang, J. M. (2005) · The FASEB Journal · doi:10.1096/fj.05-4578fje · Cited by 92
“In addition, microglial cells have been documented to phagocytose fibrillary Aβ (52–54) and to break isolated senile plaques in vitro (55).”
BackgroundCui, Y., Le, Y., Yazawa, H., Gong, W., & Wang, J. M. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.72.4.628 · Cited by 79
“Cultured rodent microglial cells and human monocytes have been shown to internalize A 42 peptides [79–81], and A 42 taken by rat microglial cells could be degraded [82, 83].”
BackgroundDecline of immune responsiveness: A pathogenetic factor in Alzheimer’s disease?
Richartz, E., Stransky, E., Batra, A., Simon, P. D., Lewczuk, P., Buchkremer, G., BARTELS, M., & Schott, K. J. (2005) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2004.12.005 · Cited by 96
“Histopathological studies on AD microglia showd altered morphology indicating a functional impairment ( De Witt et al. 1998; Sasaki et al. 1997).”
BackgroundHinkerohe, D., Smikalla, D., Haghikia, A., Heupel, K., Haase, C., Dermietzel, R., & Faustmann, P. (2005) · Glia · doi:10.1002/glia.20223 · Cited by 91
“microglial activation under certain conditions initiating and regulating microglial function, differentiation, and deactivation (Aloisi et al., 1997; DeWitt et al., 1998).”
BackgroundGlial hemichannels and their involvement in aging and neurodegenerative diseases
Orellana, J. A., Rommy von Bernhardi, M., Giaume, C., & Sáez, J. C. (2012) · Reviews in the Neurosciences · doi:10.1515/revneuro-2011-0065 · Cited by 88
Chang, J., Qian, Z., Wang, B., Cao, J., Zhang, S., Jiang, F., Kong, R., Yu, X. H., Cao, X., Yang, L., et al. (2023) · Cell Communication and Signaling · doi:10.1186/s12964-022-01036-6 · Cited by 94
“On the other hand, astrocytes also have beneficial effects in demyelinating diseases [59].”
BackgroundThe Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease
Drew, S. C. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00317 · Cited by 93
“…2009), disruption of native metal binding sites, for example by treatment of crude brain homogenates by denaturation at 97◦C and 3mM sodium azide (DeWitt et al., 1998; Dong et al., 2003), may still lead to the release of metal ions from themany hundreds of proteins that are also found within…”
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Neuroglial Roots of Neurodegenerative Diseases?
Rodríguez, J., & Verkhratsky, A. (2011) · Molecular Neurobiology · doi:10.1007/s12035-010-8157-x · Cited by 77
“Reactive astrogliosis in AD can be triggered by extracellular accumulation of β-amyloid peptide (Aβ); both aggregated β-amyloid and amyloid plaques isolated from human AD brains induced astrogliotic reactions in vitro [94].”
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“Moreover, astrocytes can also modulate microglial responses to Aβ [55, 58, 59].”
HIV-infection of the central nervous system: the tightrope walk of innate immunity
Speth, C., Dierich, M. P., & Sopper, S. (2004) · Molecular Immunology · doi:10.1016/j.molimm.2004.06.018 · Cited by 72
Nitric oxide in the cerebral cortex of amyloid-precursor protein (SW) Tg2576 transgenic mice
Rodrigo, J., Fernández‐Vizarra, P., Castro‐Blanco, S., Bentura, M. L., Nieto, M., Gómez‐Isla, T., Martínez‐Murillo, R., Martı́nez, A., Serrano, J., & Fernández, A. P. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.06.030 · Cited by 70
A unique type of GSK-3 inhibitor brings new opportunities to the clinic
Licht-Murava, A., Paz, R., Vaks, L., Avrahami, L., Plotkin, B., Eisenstein, M., & Eldar-Finkelman, H. (2016) · Science Signaling · doi:10.1126/scisignal.aah7102 · Cited by 78
Relationship Between Obesity, Alzheimer’s Disease, and Parkinson’s Disease: an Astrocentric View
Martín-Jiménez, C., Gaitán-Vaca, D. M., Echeverría, V., González, J., & Barreto, G. E. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0193-8 · Cited by 80
Antioxidant protection and neurodegenerative disease: The role of amyloid-β and tau
Castellani, R. J., Lee, H., Perry, G. L., & Smith, M. A. (2006) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/153331750602100213 · Cited by 72
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Metadata
- Authors
- DeWitt, D. A., Perry, G., Cohen, M., Doller, C., & Silver, J.
- Affiliations
- Case Western Reserve University (US)
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 1998-02
- Volume
- 149
- Issue
- 2
- Pages
- 329-340
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W2164956116
- Cited by
- 261
- References
- 69
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 11 · 2022: 6 · 2021: 12 · 2020: 3 · 2019: 7 · 2018: 8 · 2017: 6 · 2016: 12 · 2015: 13 · 2014: 11 · 2013: 8 · 2012: 13
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Scholars Crossing (Liberty University) (submittedVersion)
- Funders
- National Institutes of Health (5r01ag009287-08)
- National Institute on Aging (AG-00105-11A1, T32AG000105, AG 09287)
- National Institute of Neurological Disorders and Stroke (NS 25713)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- astrocytes, microglia, phagocytosis, amyloid plaques, Alzheimer's disease, plaque clearance, astrocyte-microglia interaction, conditioned medium, diffusible factors, latex bead phagocytosis, fibroblasts
- MeSH terms
- Alzheimer Disease, Animals, Animals, Newborn, Astrocytes, Brain, Cells, Cultured, Cerebral Cortex, Frontal Lobe, Humans, Phagocytosis, Temporal Lobe, Rats, Sprague-Dawley, Microglia, Coculture Techniques, Rats, Plaque, Amyloid
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