＜Poster＞Pyroglutamate formation at the N-termini of ABri molecules in familial British dementia is not restricted to the central nervous system
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概要
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Amyloid molecules harboring pyroglutamate （pGlu） residue at the N-termini are considered to beimportant for the development of cerebral amyloidosis such as Alzheimer’s disease and thought to be eitherspontaneously generated or being catalyzed by glutaminyl cyclase. Familial British dementia （FBD） is an autosomaldominant form of dementia neuropathologically characterized by parenchymal amyloid and preamyloid deposits,extensive cerebral amyloid angiopathy, and neurofi brillary tangles. FBD is caused by a stop to Arg mutation in theBRI2 gene, generating de novo created amyloid molecule ABri which accumulates in FBD brains but is not presentin the normal population. Soluble ABri molecules present in the circulation of carriers of the BRI2 mutation are 34amino acids long exclusively harboring Glu residue at the N-termini （ABri1-34E）, whereas water- and formic acidsolubleABri molecules extracted from FBD brains have abundant ABri species bearing pGlu residue （ABri1-34pE）,suggesting that pyroglutamate formation occurs at the site of deposition. In order to further clarify the mechanism（s）of ABri deposition, we studied whether pyroglutamate formation indeed occurs outside the central nervous systemtaking advantage that FBD is also a systemic amyloidosis. Soluble and fibrillar ABri molecules extracted fromsystemic organs and analyzed biochemically using a combination of immunoprecipitation, mass spectrometry, andwestern blot analysis were oligomeric in size and contained a large proportion of ABri1-34pE. The data indicate thatpyroglutamate formation at the N-termini of ABri molecules is an early step in the process of FBD amyloid deposition,and its formation is not restricted to the central nervous system.
著者
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Tamaoka Akira
Department Of Neurology Institute Of Clinical Medicine University Of Tsukuba
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Tamaoka Akira
Department Of Neurology University Of Tsukuba Graduate School Of Comprehensive Human Science
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Ghiso Jorge
Department of Pathology, New York University School of Medicine
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Tomidokoro Yasushi
Department of Clinical Sciences Tsukuba University
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Frangione Blas
Department of Pathology, New York University School of Medicine
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Rostagno Agueda
Department of Pathology, New York University School of Medicine
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Ghiso Jorge
Department Of Pathology New York University School Of Medicine
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Revesz Tamas
Queen Square Brain Bank For Neurological Disorders Department Of Molecular Neuroscience Ucl Institut
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Frangione Blas
Department Of Pathology New York University School Of Medicine
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Rostagno Agueda
Department Of Pathology New York University School Of Medicine
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Holton Janice
UCL Institute of Neurology, University College of London
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Lashley Tammaryn
UCL Institute of Neurology, University College of London
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Revesz Tamas
UCL Institute of Neurology, University College of London
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Holton Janice
Ucl Institute Of Neurology University College Of London
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Lashley Tammaryn
Ucl Institute Of Neurology University College Of London
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