TgCRND8 Amyloid Precursor Protein Transgenic Mice Exhibit an Altered -Secretase Processing and an Aggressive, Additive Amyloid Patho
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- 作者：Gregory D. Van Vickle ; Chera L. Esh ; Walter M. Kalback ; R. Lyle Patton ; Dean C. Luehrs ; Tyler A. Kokjohn ; Frederick G. Fifield ; Paul E. Fraser ; David Westaway ; Joanne McLaurin ; John Lopez ; Daniel Brun
- 刊名：Biochemistry
- 出版年：2007
- 出版时间：September 11, 2007
- 年：2007
- 卷：46
- 期：36
- 页码：10317 - 10327
- 全文大小：763K
- 年卷期：v.46,no.36(September 11, 2007)
- ISSN：1520-4995
文摘
We investigated the morphology and biochemistry of the amyloid-
beta2.gif" BORDER=0 ALIGN="middle"> (Abeta2.gif" BORDER=0 ALIGN="middle">) peptides producedin TgCRND8 Tg mice carrying combined amyloid precursor protein (APP) Swedish (K670M/N671L)and Indiana (V717F) mutations. Histological analyses employing amyloid-specific staining and electronmicroscopy revealed that the TgCRND8 Tg mice produce an aggressive pathology, evident as early as 3months of age, that is a composite of core plaques and peculiar floccular diffuse parenchymal deposits.The Abeta2.gif" BORDER=0 ALIGN="middle"> peptides were purified using combined FPLC-HPLC, Western blots, and immunoprecipitationmethods 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 ofsecretase processing, yielding a C-terminal fragment pattern that is substantially different from that observedin sporadic Alzheimer's disease (AD). This modified processing pattern generated longer Abeta2.gif" BORDER=0 ALIGN="middle"> peptides, aswell as those ending at residues 40/42/43, which may partially explain the early onset and destructivenature of familial AD caused by APP mutations. Despite an aggressive pathology that extended to thecerebellum and white matter, these animals tolerated the presence of an imposing amount of Abeta2.gif" BORDER=0 ALIGN="middle"> load. Abeta2.gif" BORDER=0 ALIGN="middle">immunization resulted in an impressive 7-fold reduction in the number of amyloid core plaques and, aspreviously demonstrated, a significant memory recovery. However, given the phylogenetic distance andthe differences in APP processing and Abeta2.gif" BORDER=0 ALIGN="middle"> chemistry between Tg mice and AD, caution should be appliedin projecting mouse therapeutic interventions onto human subjects.
beta2.gif" BORDER=0 ALIGN="middle"> (Abeta2.gif" BORDER=0 ALIGN="middle">) peptides producedin TgCRND8 Tg mice carrying combined amyloid precursor protein (APP) Swedish (K670M/N671L)and Indiana (V717F) mutations. Histological analyses employing amyloid-specific staining and electronmicroscopy revealed that the TgCRND8 Tg mice produce an aggressive pathology, evident as early as 3months of age, that is a composite of core plaques and peculiar floccular diffuse parenchymal deposits.The Abeta2.gif" BORDER=0 ALIGN="middle"> peptides were purified using combined FPLC-HPLC, Western blots, and immunoprecipitationmethods 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 ofsecretase processing, yielding a C-terminal fragment pattern that is substantially different from that observedin sporadic Alzheimer's disease (AD). This modified processing pattern generated longer Abeta2.gif" BORDER=0 ALIGN="middle"> peptides, aswell as those ending at residues 40/42/43, which may partially explain the early onset and destructivenature of familial AD caused by APP mutations. Despite an aggressive pathology that extended to thecerebellum and white matter, these animals tolerated the presence of an imposing amount of Abeta2.gif" BORDER=0 ALIGN="middle"> load. Abeta2.gif" BORDER=0 ALIGN="middle">immunization resulted in an impressive 7-fold reduction in the number of amyloid core plaques and, aspreviously demonstrated, a significant memory recovery. However, given the phylogenetic distance andthe differences in APP processing and Abeta2.gif" BORDER=0 ALIGN="middle"> chemistry between Tg mice and AD, caution should be appliedin projecting mouse therapeutic interventions onto human subjects.