β-Amyloid Stimulates Murine Postnatal and Adult Microglia Cultures in a Unique Manner

Floden, Angela M.; Combs, Colin K.

doi:10.1523/jneurosci.4822-05.2006

Cited by 103 publications

(95 citation statements)

References 35 publications

(46 reference statements)

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“…Activated microglia have been observed around senile plaques in the brains of AD patients 38,39) and in fact microglia are activated by fibril Aβ. 40) Although microglia are usually in a state of rest and do not damage neurons and tissue, activated microglia can induce neuronal cell and tissue injury by inducing inflammation via the release of inflammatory cytokines, including tumor necrosis factor α and interleukin-1 (IL-1).…”

Section: Discussionmentioning

confidence: 99%

Shuttling Protein Nucleolin Is a Microglia Receptor for Amyloid Beta Peptide 1-42

Ozawa

Nakamura

Koike

et al. 2013

Biological & Pharmaceutical Bulletin

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Amyloid-beta peptide 1-42 (Aβ42) plays a key role in the neurotoxicity found in Alzheimer's disease. Mononuclear phagocytes in the brain (microglia), can potentially clear Aβ via phagocytosis. Recently, the shuttling-protein nucleolin has been shown to possess scavenger receptor-activity. Here, we investigated whether this receptor interacts specifically with Aβ type 1-42 and mediates its phagocytosis by microglia. While monomeric and fibril Aβ42 were phagocytosed by mouse microglial EOC2 cells, amyloid β peptide 1-40 (Aβ40) was only weakly phagocytosed. Surface plasmon-resonance analysis revealed that nucleolin strongly associates with Aβ42, but only weakly associates with Aβ40. Immunofluorescence staining of antinucleolin antibody revealed that EOC2 cells and rat primary microglia express nucleolin on their cell surfaces. Further, pretreating EOC2 cells with anti-nucleolin antibody, but not immunoglobulin G (IgG), inhibited phagocytosis of monomeric Aβ42 by microglia. Additionally, nucleolin-transfected HEK293 cells phagocytosed monomeric and fibril Aβ42 but not monomeric and fibril Aβ40. Moreover, AGRO, a nucleolin-specific oligonucleotide aptamer, inhibited phagocytosis of monomeric and fibril Aβ42, but not monomeric and fibril Aβ40. These results indicate that nucleolin is a receptor that allows microglia to recognize monomeric and fibril Aβ42.

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Section: Discussionmentioning

confidence: 99%

Shuttling Protein Nucleolin Is a Microglia Receptor for Amyloid Beta Peptide 1-42

Ozawa

Nakamura

Koike

et al. 2013

Biological & Pharmaceutical Bulletin

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“…Microglial phagocytosis of FAM-labeled A␤1-42 (FAM-A␤) (AnaSpec) was measured by plate-based assay as previously described (Floden and Combs, 2006). In brief, cells were plated at a density of 50,000 per well.…”

Section: Methodsmentioning

confidence: 99%

“…Phagocytosis of aged FAM-labeled A␤1-42 by microglia in vitro was assayed as previously described by Floden and Combs (2006), and controlled by laser confocal microscopy and immunoprecipitation of A␤ in lysates of microglial cells. Aggregation of A␤ upon aging was verified by Western blot analysis (Fig.…”

Section: Modulation Of Microglial A␤1-42 Phagocytosis By the Lxr Agonmentioning

confidence: 99%

Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis

Terwel¹,

Steffensen²,

Verghese³

et al. 2011

J. Neurosci.

165

115

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Liver X receptors (LXRs) regulate immune cell function and cholesterol metabolism, both factors that are critically involved in Alzheimer's disease (AD). To investigate the therapeutic potential of long-term LXR activation in amyloid-␤ (A␤) peptide deposition in an AD model, 13-month-old, amyloid plaque-bearing APP23 mice were treated with the LXR agonist TO901317. Postmortem analysis demonstrated that TO901317 efficiently crossed the blood-brain barrier. Insoluble and soluble A␤ levels in the treated APP23 mice were reduced by 80% and 40%, respectively, compared with untreated animals. Amyloid precursor protein (APP) processing, however, was hardly changed by the compound, suggesting that the observed effects were instead mediated by A␤ disposal. Despite the profound effect on A␤ levels, spatial learning in the Morris water maze was only slightly improved by the treatment. ABCA1 (ATP-binding cassette transporter 1) and apolipoprotein E (ApoE) protein levels were increased and found to be primarily localized in astrocytes. Experiments using primary microglia demonstrated that medium derived from primary astrocytes exposed to TO901317 stimulated phagocytosis of fibrillar A␤. Conditioned medium from TO901317-treated ApoE Ϫ/Ϫ or LXR␣ Ϫ/Ϫ astrocytes did not increase phagocytosis of A␤. In APP23 mice, long-term treatment with TO901317 strongly increased the association of microglia and A␤ plaques. Short-term treatment of APP/PS1 mice with TO901317 also increased this association, which was dependent on the presence of LXR␣ and was accompanied by increased ApoE lipidation. Together, these data suggest that astrocytic LXR␣ activation and subsequent release of ApoE by astrocytes is critical for the ability of microglia to remove fibrillar A␤ in response to treatment with TO901317.

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“…The key pathogenetic event in Alzheimer is accumulation of amyloid ␤ (A␤) 3 ; however, how this protein, whether in the soluble or fibrillar form, triggers neuroinflammation is as yet an open question (2)(3)(4). Participation of microglia to A␤-mediated neuronal loss is debated as this cell type may have a protective effect by phagocytosing amyloid fibrils (5-7), but on the other hand, there is also evidence that inflammatory cytokines or oxidant species released from microglia might be detrimental for neurons (8 -10).…”

mentioning

confidence: 99%

Activation of Microglia by Amyloid β Requires P2X7 Receptor Expression

Sanz

Chiozzi²,

Ferrari³

et al. 2009

The Journal of Immunology

255

226

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Extracellular ATP is a mediator of intercellular communication and a danger signal. Release of this and other nucleotides modulates microglia responses via P2Y and P2X receptors, among which the P2X7 subtype stands out for its proinflammatory activity and for up-regulation in a transgenic model of Alzheimer disease and in brains from Alzheimer disease patients. Here we show that amyloid β (Aβ) triggered increases in intracellular Ca2+ ([Ca2+]i), ATP release, IL-1β secretion, and plasma membrane permeabilization in microglia from wild-type but not from P2X7-deleted mice. Likewise, intra-hippocampal injection of Aβ caused a large accumulation of IL-1β in wild-type but not in P2X7−/− mice. These observations suggest that Aβ activates a purinergic autocrine/paracrine stimulatory loop of which the P2X7 receptor is an obligate component. Identification of the P2X7 receptor as a non-dispensable factor of Aβ-mediated microglia stimulation may open new avenues for the treatment of Alzheimer disease.

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β-Amyloid Stimulates Murine Postnatal and Adult Microglia Cultures in a Unique Manner

Cited by 103 publications

References 35 publications

Shuttling Protein Nucleolin Is a Microglia Receptor for Amyloid Beta Peptide 1-42

Shuttling Protein Nucleolin Is a Microglia Receptor for Amyloid Beta Peptide 1-42

Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis

Activation of Microglia by Amyloid β Requires P2X7 Receptor Expression

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