TgCRND8 Amyloid Precursor Protein Transgenic Mice Exhibit an Altered γ-Secretase Processing and an Aggressive, Additive Amyloid Pathology Subject to Immunotherapeutic Modulation
| Autor: | Marissa Poston, Frederick G Fifield, Walter M. Kalback, Tyler A Kokjohn, Chera L Esh, Alex E Roher, Gregory D. Van Vickle, Daniel C. Brune, Dean C. Luehrs, R. Lyle Patton, Amanda J. Newel, David Westaway, Thomas G. Beach, Joanne McLaurin, John Lopez, Paul E Fraser |
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| Rok vydání: | 2007 |
| Předmět: |
Genetically modified mouse
Amyloid Molecular Sequence Data BACE1-AS Mice Transgenic Plaque Amyloid Biochemistry Amyloid beta-Protein Precursor Mice Alzheimer Disease mental disorders Amyloid precursor protein Animals Amino Acid Sequence Benzothiazoles Chromatography High Pressure Liquid Gamma secretase biology Chemistry P3 peptide Brain Molecular biology Blot Thiazoles Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization biology.protein Immunotherapy Amyloid Precursor Protein Secretases Protein Processing Post-Translational Amyloid precursor protein secretase |
| Zdroj: | Biochemistry. 46:10317-10327 |
| ISSN: | 1520-4995 0006-2960 |
| Popis: | We investigated the morphology and biochemistry of the amyloid-beta (Abeta) peptides produced in TgCRND8 Tg mice carrying combined amyloid precursor protein (APP) Swedish (K670M/N671L) and Indiana (V717F) mutations. Histological analyses employing amyloid-specific staining and electron microscopy revealed that the TgCRND8 Tg mice produce an aggressive pathology, evident as early as 3 months of age, that is a composite of core plaques and peculiar floccular diffuse parenchymal deposits. The Abeta peptides were purified using combined FPLC-HPLC, Western blots, and immunoprecipitation methods and characterized by MALDI-TOF/SELDI-TOF mass spectrometry. The C-terminal APP peptides, assessed by Western blot experiments and mass spectrometry, suggested an alteration in the order of secretase processing, yielding a C-terminal fragment pattern that is substantially different from that observed in sporadic Alzheimer's disease (AD). This modified processing pattern generated longer Abeta peptides, as well as those ending at residues 40/42/43, which may partially explain the early onset and destructive nature of familial AD caused by APP mutations. Despite an aggressive pathology that extended to the cerebellum and white matter, these animals tolerated the presence of an imposing amount of Abeta load. Abeta immunization resulted in an impressive 7-fold reduction in the number of amyloid core plaques and, as previously demonstrated, a significant memory recovery. However, given the phylogenetic distance and the differences in APP processing and Abeta chemistry between Tg mice and AD, caution should be applied in projecting mouse therapeutic interventions onto human subjects. |
| Databáze: | OpenAIRE |
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