Astrocytes Regulate Microglial Phagocytosis of Senile Plaque Cores of Alzheimer's Disease

DeWitt, David A.; Perry, George; Cohen, Mark; Doller, Catherine; Silver, Jerry

doi:10.1006/exnr.1997.6738

Cited by 261Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsPhagocytosis and Immune Regulation

Astrocytes Regulate Microglial Phagocytosis of Senile Plaque Cores of Alzheimer's Disease

DeWitt, David A., Perry, George, Cohen, Mark, Doller, Catherine, Silver, Jerry·1998·Experimental Neurology

DOI 10.1006/exnr.1997.6738

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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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Popovich, P. G., Guan, Z., Wei, P. Y., Huitinga, I., van Rooijen, N., & Stokes, B. T. (1999) · Experimental Neurology · doi:10.1006/exnr.1999.7118 · Cited by 692 · see citing works
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Background
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Human astrocytes in the diseased brain
Dossi, E., Vasile, F., & Rouach, N. (2018) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.02.001 · Cited by 250 · see citing works
Role of Astrocytes in Brain Function and Disease
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Background
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Background
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Background
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Background
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“Interestingly, the local presence of astrocytes inhibited the microglial ability to ingest plaques or A in vitro [19,54].”
Background
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Background
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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 · see citing works
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Background
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“…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).”
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Background
Altered 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 · see citing works
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Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer’s disease
Yumoto, S., Kakimi, S., Ohsaki, A., & Ishikawa, A. (2009) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2009.07.023 · Cited by 166 · see citing works
Role of Neuroinflammation in Adult Neurogenesis and Alzheimer Disease: Therapeutic Approaches
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Background
“Targeting astrocytes in CNS injury and disease: A translational research approach”
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Self-citation
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Background
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Collingwood, 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 · see citing works
“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-citation
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Self-citation
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“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).”
Background
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“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 146 · see citing works
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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 139 · see citing works
“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-citation
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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 · see citing works
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Rommy von Bernhardi, M. (2007) · Neurotoxicity Research · doi:10.1007/bf03033906 · Cited by 138 · see citing works
“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).”
Background
Neuropathology 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 · see citing works
“immobilized amyloid- elicit neurotoxity in vivo or in vitro [10, 17, 20] (Fig.”
BackgroundSelf-citation
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Eskes, C., Honegger, P., Juillerat‐Jeanneret, L., & Monnet‐Tschudi, F. (2001) · Glia · doi:10.1002/glia.10019 · Cited by 122 · see citing works
β Amyloid peptide (Aβ 42 ) is internalized via the G‐protein‐coupled receptor FPRL1 and forms fibrillar aggregates in macrophages 1
Yazawa, H., Yu, Z., 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 137 · see citing works
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 · see citing works
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 117 · see citing works
“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.”
BackgroundInfluential
Involvement of microglia–neuron interactions in the tumor necrosis factor‐α release, microglial activation, and neurodegeneration induced by trimethyltin
Eskes, C., Juillerat-Jeanneret, L., Leuba, G., Honegger, P., & Monnet-Tschudi, F. (2003) · Journal of Neuroscience Research · doi:10.1002/jnr.10508 · Cited by 114 · see citing works
“This observation is in agreement with a previous study showing that the presence of astrocytes decreased microglial reactivity (DeWitt et al., 1998).”
Result
Role of Formyl Peptide Receptor–Like 1 (FPRL1/FPR2) in Mononuclear Phagocyte Responses in Alzheimer Disease
Iribarren, P., Zhou, Y., Hu, J., Le, Y., & Wang, J. M. (2005) · Immunologic Research · doi:10.1385/ir:31:3:165 · Cited by 104 · see citing works
“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).”
Result
Effects of estrogen receptor agonists on regulation of the inflammatory response in astrocytes from young adult and middle-aged female rats
Lewis, 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 · see citing works
“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 112 · see citing works
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 · see citing works
Astrocyte‐released cytokines induce ramification and outward K<sup>+</sup> channel expression in microglia via distinct signalling pathways
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 · see citing works
“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).”
Background
Lactate induces tumour necrosis factor‐α, interleukin‐6 and interleukin‐1β release in microglial‐ and astroglial‐enriched primary cultures
Andersson, A. K., Rönnbäck, L., & Hansson, E. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03132.x · Cited by 108 · see citing works
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 115 · see citing works
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 110 · see citing works
“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).”
Background
Mechanisms of amyloid plaque pathogenesis
Fiala, J. C. (2007) · Acta Neuropathologica · doi:10.1007/s00401-007-0284-8 · Cited by 98 · see citing works
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 120 · see citing works
Role of interleukin-1 in prion disease-associated astrocyte activation.
Schultz, J., Schwarz, A., Neidhold, S., Burwinkel, M., Riemer, C., Simon, D., Kopf, M., Otto, M., & Baier, M. (2004) · American Journal of Pathology · doi:10.1016/s0002-9440(10)63331-7 · Cited by 101 · see citing works
Amyloid‐β‐induced toxicity of primary neurons is dependent upon differentiation‐associated increases in tau and cyclin‐dependent kinase 5 expression
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 84 · see citing works
Self-citation
Aβ 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 · see citing works
“, 2009) and strogliosis (DeWitt et al., 1998).”
Impaired Performance of Female APP/PS1 Mice in the Morris Water Maze Is Coupled with Increased Aβ Accumulation and Microglial Activation
Gallagher, J. J., Minogue, A. M., & Lynch, M. A. (2012) · Neurodegenerative Diseases · doi:10.1159/000337458 · Cited by 99 · see citing works
Metabolic Regulation of Glial Phenotypes: Implications in Neuron–Glia Interactions and Neurological Disorders
Afridi, R., Kim, J., Rahman, M. H., & Suk, K. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00020 · Cited by 98 · see citing works
CpG‐containing oligodeoxynucleotide promotes microglial cell uptake of amyloid β 1–42 peptide by up‐regulating the expression of the G‐protein‐coupled receptor mFPR2
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 73 · see citing works
“In addition, microglial cells have been documented to phagocytose fibrillary Aβ (52–54) and to break isolated senile plaques in vitro (55).”
Background
Potential role of the formyl peptide receptor-like 1 (FPRL1) in inflammatory aspects of Alzheimer's disease
Cui, Y., Le, Y., Yazawa, H., Gong, W., & Wang, J. M. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.72.4.628 · Cited by 78 · see citing works
“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].”
Background
Decline 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 95 · see citing works
“Histopathological studies on AD microglia showd altered morphology indicating a functional impairment ( De Witt et al. 1998; Sasaki et al. 1997).”
Background
Effects of cytokines on microglial phenotypes and astroglial coupling in an inflammatory coculture model
Hinkerohe, D., Smikalla, D., Haghikia, A., Heupel, K., Haase, C., Dermietzel, R., & Faustmann, P. (2005) · Glia · doi:10.1002/glia.20223 · Cited by 91 · see citing works
“microglial activation under certain conditions initiating and regulating microglial function, differentiation, and deactivation (Aloisi et al., 1997; DeWitt et al., 1998).”
Background
Glial 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 86 · see citing works
Transplantation of A2 type astrocytes promotes neural repair and remyelination after spinal cord injury
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 91 · see citing works
“On the other hand, astrocytes also have beneficial effects in demyelinating diseases [59].”
Background
The 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 · see citing works
“…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…”
BackgroundMethodInfluential
Clomipramine treatment reversed the glial pathology in a chronic unpredictable stress-induced rat model of depression
Liu, Q., Li, B., Zhu, H., Wang, Y., Yu, J. M., & Wu, G.-C. (2009) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2009.06.010 · Cited by 77 · see citing works
Neuroglial Roots of Neurodegenerative Diseases?
Rodriguez, J. J., & Verkhratsky, A. (2010) · Molecular Neurobiology · doi:10.1007/s12035-010-8157-x · Cited by 72 · see citing works
“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].”
Background
IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia
Rivera-Escalera, F., Pinney, J. J., Owlett, L., Ahmed, H., Thakar, J., Olschowka, J. A., Elliott, M. R., & O’Banion, M. K. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1645-7 · Cited by 75 · see citing works
“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., & Sopper, S. (2005) · Molecular Immunology · doi:10.1016/j.molimm.2004.06.018 · Cited by 74 · see citing works
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 · see citing works
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 77 · see citing works
Relationship Between Obesity, Alzheimer’s Disease, and Parkinson’s Disease: an Astrocentric View
Martín-Jiménez, C., Gaitán-Vaca, D. M., Echeverrı́a, V., González, J., & Barreto, G. E. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0193-8 · Cited by 77 · see citing works
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 70 · see citing works
Self-citation
Expression of nicotinic receptors on primary cultures of rat astrocytes and up-regulation of the α7, α4 and β2 subunits in response to nanomolar concentrations of the β-amyloid peptide1–42
Xiu, J., Nordberg, A. K., Zhang, J., & Guan, Z.-Z. (2005) · Neurochemistry International · doi:10.1016/j.neuint.2005.04.023 · Cited by 81 · see citing works

Authors: DeWitt, D. A., Perry, G., Cohen, M., Doller, C., & Silver, J.
Affiliations: Case Western Reserve University (US)
ORCID: Perry, George
Cohen, Mark
Silver, Jerry
Venue: Experimental Neurology
Publisher: Elsevier BV
Published: 1998-02
Volume: 149
Issue: 2
Pages: 329-340
ISSN: 0014-4886 (ISSN-L)
DOI: 10.1006/exnr.1997.6738
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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
Health Sciences › Medicine › Physiology › 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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Astrocytes Regulate Microglial Phagocytosis of Senile Plaque Cores of Alzheimer's Disease

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