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Identification and structural characterisation of carboxy-terminal polypeptides and antibody epitopes of Alzheimer's amyloid precursor protein using high-resolution mass spectrometry

Identification and structural characterisation of carboxy-terminal polypeptides and antibody epitopes of Alzheimer's amyloid precursor protein using high-resolution mass spectrometry

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TIAN, Xiaodan, Roxana CECAL, JoAnne MCLAURIN, Marilena MANEA, Raluca STEFANESCU, Sandra GRAU, Mona HARNASCH, Sarah AMIR, Michael EHRMANN, Peter St GEORGE-HYSLOP, Markus KOHLMANN, Michael PRZYBYLSKI, 2005. Identification and structural characterisation of carboxy-terminal polypeptides and antibody epitopes of Alzheimer's amyloid precursor protein using high-resolution mass spectrometry. In: European Journal of Mass Spectrometry. 11(1), pp. 547-556. ISSN 1356-1049

@article{Tian2005Ident-17564, title={Identification and structural characterisation of carboxy-terminal polypeptides and antibody epitopes of Alzheimer's amyloid precursor protein using high-resolution mass spectrometry}, year={2005}, doi={10.1255/ejms.722}, number={1}, volume={11}, issn={1356-1049}, journal={European Journal of Mass Spectrometry}, pages={547--556}, author={Tian, Xiaodan and Cecal, Roxana and McLaurin, JoAnne and Manea, Marilena and Stefanescu, Raluca and Grau, Sandra and Harnasch, Mona and Amir, Sarah and Ehrmann, Michael and George-Hyslop, Peter St and Kohlmann, Markus and Przybylski, Michael} }

<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/17564"> <dcterms:bibliographicCitation>Publ. in: European journal of mass spectrometry ; 11 (2005), 5. - S. 547-556</dcterms:bibliographicCitation> <dc:contributor>Przybylski, Michael</dc:contributor> <dc:creator>Manea, Marilena</dc:creator> <dc:creator>Kohlmann, Markus</dc:creator> <dc:contributor>Harnasch, Mona</dc:contributor> <dc:contributor>Ehrmann, Michael</dc:contributor> <dc:creator>Grau, Sandra</dc:creator> <dcterms:issued>2005</dcterms:issued> <dc:contributor>Cecal, Roxana</dc:contributor> <dc:contributor>Manea, Marilena</dc:contributor> <dc:contributor>Tian, Xiaodan</dc:contributor> <bibo:uri rdf:resource="http://kops.uni-konstanz.de/handle/123456789/17564"/> <dc:contributor>George-Hyslop, Peter St</dc:contributor> <dc:language>eng</dc:language> <dc:contributor>Grau, Sandra</dc:contributor> <dc:creator>McLaurin, JoAnne</dc:creator> <dc:creator>Harnasch, Mona</dc:creator> <dcterms:abstract xml:lang="eng">Alzheimer's disease (AD) is the most common cause for human age-related dementia, characterised by formation of diffuse plaques in brain that are directly involved in AD pathogenesis. The major component of AD plaques is beta-amyloid, a 40 to 42 amino acid polypeptide derived from the amyloid precursor protein (APP) by proteolytic degradation involving the specific proteases, beta-and gamma-secretase acting at the N- and C- terminal cleavage site, respectively. In this study we have prepared polypeptides comprising the carboxy-terminal and transmembrane sequences of APP, by bacterial expression and chemical synthesis, as substrates for studying the C-terminal processing of APP and its interaction with the gamma-secretase complex. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) was used as a major tool for structure analysis. Immunisation of transgenic mouse models of AD with Abeta42 has been recently shown to be effective to inhibit and disaggregate Abeta-fibrils, and to reduce AD-related neuropathology and memory impairments. However, the mechanism underlying these therapeutic effects has been as yet unclear. Using proteolytic epitope excision from immune complexes in combination with FT-ICR-MS, we identified the epitope recognised by the therapeutically active antibody as the N-terminal Abeta(4-10) sequence; this soluble, nontoxic epitope opens new lead structures for AD vaccine development. A monoclonal antibody (Jonas; JmAb) directed against the cytosolic APP domain was used in studies of APP biochemistry and metabolism. Here we report the identification of the epitope recognised by the JmAb, using the combination of epitope excision and peptide mapping by FT-ICR-MS. The epitope was determined to be located at the C-terminal APP(740-747) sequence; it was confirmed by ELISA binding assays and authentic synthetic peptides and will be an efficient tool in the development of new specific vaccines. These results demonstrate high-resolution FT-ICR-MS as a powerful method for characterising biochemical pathways and molecular recognition structures of APP.</dcterms:abstract> <dc:creator>Amir, Sarah</dc:creator> <dc:rights>deposit-license</dc:rights> <dc:creator>Cecal, Roxana</dc:creator> <dc:contributor>Amir, Sarah</dc:contributor> <dc:contributor>Kohlmann, Markus</dc:contributor> <dc:creator>Ehrmann, Michael</dc:creator> <dc:creator>Tian, Xiaodan</dc:creator> <dc:contributor>McLaurin, JoAnne</dc:contributor> <dc:creator>Stefanescu, Raluca</dc:creator> <dc:creator>Przybylski, Michael</dc:creator> <dcterms:rights rdf:resource="http://nbn-resolving.org/urn:nbn:de:bsz:352-20140905103605204-4002607-1"/> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2012-01-13T07:33:01Z</dcterms:available> <dc:creator>George-Hyslop, Peter St</dc:creator> <dc:contributor>Stefanescu, Raluca</dc:contributor> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2012-01-13T07:33:01Z</dc:date> <dcterms:title>Identification and structural characterisation of carboxy-terminal polypeptides and antibody epitopes of Alzheimer's amyloid precursor protein using high-resolution mass spectrometry</dcterms:title> </rdf:Description> </rdf:RDF>

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