[Beta]-amyloid-mediated nitric oxide release from rat microglia by ligation of the integrin Mac-1

dc.contributor.advisor Etsuro Uemura
dc.contributor.author Goodwin, Jeffrey
dc.contributor.department Veterinary Anatomy
dc.date 2018-08-23T15:35:54.000
dc.date.accessioned 2020-06-30T07:13:37Z
dc.date.available 2020-06-30T07:13:37Z
dc.date.copyright Mon Jan 01 00:00:00 UTC 1996
dc.date.issued 1996
dc.description.abstract <p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized histopathologically by a loss of neurons and an accumulation of [beta]-amyloid plaques, neurofibrillary tangles, dystrophic neurites, and reactive glial cells. While most previous studies on the neurodegeneration of AD have focused on neuronal cells and direct [beta]-amyloid-mediated neurotoxicity, few have focused on the role of reactive glial cells in [beta]-amyloid-mediated neurotoxicity. In the present study nitric oxide release from cultured rat microglia was examined by exposing the cells to synthetic [beta]-amyloid peptides ([beta]25-35 and [beta]1-40) alone and in combination with cytokines. Assessment of microglial release of nitric oxide was based on the colorimetric assay for nitrite in the culture medium and histochemistry for nitric oxide synthase. Of the cytokines tested, only IFN-[gamma] (1000 U/ml) induced nitric oxide release from microglia. [beta]25-35 did not stimulate nitric oxide release by itself, but it did induce nitric oxide release when co-exposed with IFN-[gamma]. In contrast, [beta]1-40 did induce microglial release of nitric oxide by itself, and this effect was enhanced significantly by co-exposure with IFN-[beta] (100 U/ml). To elucidate the mechanisms involved in [beta]-amyloid mediated nitric oxide release, the binding of [beta]25-35 with the leukocyte integrin Mac-1, a cell surface receptor on microglia, was studied by observing (1) [beta]-amyloid ([beta]25-35)-mediated release of nitric oxide from cultured microglial cells following exposure to monoclonal antibodies against each subunit of Mac-1 (anti-CD18 and anti-CD11b) and (2) competitive binding assay of fluorochrome-labeled [beta]25-35 with anti-CD18 or anti-CD11b by fluorescent flow cytometry. The results demonstrate that binding of CD18 and CD11b on microglial cells are individually sufficient to elicit release of nitric oxide and that a combination of CD18 and CD11b elicit a maximal NO release. [beta]25-35 significantly reduced nitric oxide release mediated by Wt.3. In contrast, [beta]25-35 significantly increased nitric oxide release by OX42. The binding study further suggested that Wt.3 and [beta]25-35 share a common site of action on the CD18 of Mac-1. These findings warrant a further investigation into the role of microglia in the neurodegeneration of Alzheimer's disease via nitric oxide toxicity induced by the synergistic action of [beta]-amyloid (with a costimulatory factor) and mediated by the microglial surface receptor Mac-1.</p>
dc.format.mimetype application/pdf
dc.identifier archive/lib.dr.iastate.edu/rtd/11526/
dc.identifier.articleid 12525
dc.identifier.contextkey 6455420
dc.identifier.doi https://doi.org/10.31274/rtd-180813-10551
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath rtd/11526
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/64793
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/rtd/11526/r_9712554.pdf|||Fri Jan 14 18:52:25 UTC 2022
dc.subject.disciplines Medical Pathology
dc.subject.disciplines Neuroscience and Neurobiology
dc.subject.disciplines Neurosciences
dc.subject.disciplines Pathology
dc.subject.disciplines Veterinary Pathology and Pathobiology
dc.subject.keywords Veterinary anatomy
dc.title [Beta]-amyloid-mediated nitric oxide release from rat microglia by ligation of the integrin Mac-1
dc.type article
dc.type.genre dissertation
dspace.entity.type Publication
relation.isOrgUnitOfPublication a4121e11-f085-4644-b87b-31ac92e3d3c7
thesis.degree.level dissertation
thesis.degree.name Doctor of Philosophy
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