{"@context":"http://iiif.io/api/presentation/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/manifest.json","@type":"sc:Manifest","label":"Novel Amyloid Beta-Protein Degrading Enzymes. Membrane Type 1 Matrix-Metalloproteinase and Myelin Basic Protein","metadata":[{"label":"dc.description.sponsorship","value":"This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree."},{"label":"dc.format","value":"Monograph"},{"label":"dc.format.medium","value":"Electronic Resource"},{"label":"dc.identifier.uri","value":"http://hdl.handle.net/1951/55527"},{"label":"dc.language.iso","value":"en_US"},{"label":"dc.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.abstract","value":"The progressive accumulation of \u00e1-amyloid (A\u00e1) in senile plaques and in the cerebral vasculature is the hallmark of Alzheimer's disease (AD) and related disorders.  Several major pathways for A\u00e1 clearance include receptor-mediated cellular uptake, blood-brain barrier transport and direct proteolytic degradation.  My thesis focused on two novel A\u00e1 degrading enzymes- Membrane type 1 matrix metalloproteinase (MT1-MMP) and myelin basic protein (MBP). Matrix metalloproteinase 2 (MMP2) was shown to be expressed in reactive astrocytes surrounding amyloid plaques and may contribute to A\u00e1 degradation.  MT1-MMP is the physiological activator for the zymogen pro-MMP2.  In addition to MMP2, its activator MT1-MMP was also expressed in reactive astrocytes surrounding amyloid deposits in transgenic mice.  Using a cell-based system MT1-MMP overexpression can degrade exogenous A\u00e1 peptides.  Purified MT1-MMP degraded both soluble and fibrillar A\u00e1 peptides and this activity was blocked by specific MMP inhibitors.  Mass spectrometry analysis identified multiple cleavage sites on A\u00e1.  Furthermore, in situ experiments showed that purified MT1-MMP degraded parenchymal fibrillar amyloid plaques that form in the brains of transgenic mice.  Together, these findings indicate that MT1-MMP possesses A\u00e1 degrading activity in vitro.MBP is the major structural protein component of myelin sheath.  MBP possesses endogenous serine proteinase activity and can undergo autolysis.  Recently, our lab showed that MBP binds A\u00e1 and inhibits A\u00e1 fibril formation.  A\u00e1 peptides were degraded by purified human brain MBP and recombinant human MBP, but not an MBP fragment without autolytic activity.  Similarly, cells expressing MBP degraded exogenous A\u00e1 peptides.  In addition, purified MBP also degraded assembled fibrillar A\u00e1.  Mass spectrometry analysis identified multiple cleavage sites on A\u00e1.  Further, in situ experiments showed that purified MBP can degrade parenchymal amyloid plaques and cerebral vascular amyloid that form in the brains of transgenic mice.  Lastly, series of C-terminal deletion MBP proteins were tested for autolysis and A\u00e1 degradation activities to identify the responsible region.  Together, these findings indicate that purified MBP possesses A\u00e1 degrading activity in-vitro.To conclude, I characterized two novel A\u00e1 degrading enzymes in-vitro.  Further in vivo experiments are needed to investigate the role of these two A\u00e1 degrading enzymes in the pathology of AD."},{"label":"dcterms.available","value":"2015-04-24T14:52:42Z"},{"label":"dcterms.contributor","value":"Styliani-Anna E. Tsirka"},{"label":"dcterms.creator","value":"Liao, Mei-Chen"},{"label":"dcterms.dateAccepted","value":"2012-05-15T18:04:55Z"},{"label":"dcterms.dateSubmitted","value":"2012-05-15T18:04:55Z"},{"label":"dcterms.description","value":"Department of Molecular and Cellular Biology"},{"label":"dcterms.format","value":"Monograph"},{"label":"dcterms.identifier","value":"http://hdl.handle.net/1951/55527"},{"label":"dcterms.issued","value":"2010-05-01"},{"label":"dcterms.language","value":"en_US"},{"label":"dcterms.provenance","value":"Made available in DSpace on 2012-05-15T18:04:55Z (GMT). No. of bitstreams: 1\nLiao_grad.sunysb_0771E_10058.pdf: 4162684 bytes, checksum: 3392f87c7150a2391f9fd2dff9261e25 (MD5)\n  Previous issue date:    1"},{"label":"dcterms.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.subject","value":"Alzheimer disease, amyloid beta protein, membrane type 1 matrix metalloproteinase, myelin basic protein"},{"label":"dcterms.title","value":"Novel Amyloid Beta-Protein Degrading Enzymes. Membrane Type 1 Matrix-Metalloproteinase and Myelin Basic Protein"},{"label":"dcterms.type","value":"Dissertation"},{"label":"dc.type","value":"Dissertation"}],"description":"This manifest was generated dynamically","viewingDirection":"left-to-right","sequences":[{"@type":"sc:Sequence","canvases":[{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json","@type":"sc:Canvas","label":"Page 1","height":1650,"width":1275,"images":[{"@type":"oa:Annotation","motivation":"sc:painting","resource":{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/16%2F88%2F51%2F168851214539312447041010610642337760374/full/full/0/default.jpg","@type":"dctypes:Image","format":"image/jpeg","height":1650,"width":1275,"service":{"@context":"http://iiif.io/api/image/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/16%2F88%2F51%2F168851214539312447041010610642337760374","profile":"http://iiif.io/api/image/2/level2.json"}},"on":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json"}]}]}]}