TgCRND8 amyloid precursor protein transgenic mice exhibit an altered gamma-secretase processing and an aggressive, additive amyloid pathology subject to immunotherapeutic modulation.

TgCRND8 amyloid precursor protein transgenic mice exhibit an altered gamma-secretase processing and an aggressive, additive amyloid pathology subject to immunotherapeutic modulation. Research Abstract Details 

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TgCRND8 amyloid precursor protein transgenic mice exhibit an altered gamma-secretase processing and an aggressive, additive amyloid pathology subject to immunotherapeutic modulation. Abstract Text:

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 Brune,Amanda J Newel,Marissa Poston,Thomas G Beach,Alex E Roher,

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.

TgCRND8 amyloid precursor protein transgenic mice exhibit an altered gamma-secretase processing and an aggressive, additive amyloid pathology subject to immunotherapeutic modulation. Publishing Authors By Initials

GD Van Vickle,CL Esh,WM Kalback,RL Patton,DC Luehrs,TA Kokjohn,FG Fifield,PE Fraser,D Westaway,J McLaurin,J Lopez,D Brune,AJ Newel,M Poston,TG Beach,AE Roher,

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TgCRND8 amyloid precursor protein transgenic mice exhibit an altered gamma-secretase processing and an aggressive, additive amyloid pathology subject to immunotherapeutic modulation. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Biochemistry

VOLUME: 46

Page Numbers: 10317-27

Journal Abbreviation: Biochemistry

ISSN: 0006-2960

DAY: 18

MONTH: 08

YEAR: 2007

TgCRND8 amyloid precursor protein transgenic mice exhibit an altered gamma-secretase processing and an aggressive, additive amyloid pathology subject to immunotherapeutic modulation. Information

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LANGUAGE: eng

NlmUniqueID: 370623

TgCRND8 amyloid precursor protein transgenic mice exhibit an altered gamma-secretase processing and an aggressive, additive amyloid pathology subject to immunotherapeutic modulation. Keywords Mesh Terms:

KEYWORDS: Thiazoles

MESH TERMS: metabolism

Chemical & Substance for Abstract: TgCRND8 amyloid precursor protein transgenic mice exhibit an altered gamma-secretase processing and an aggressive, additive amyloid pathology subject to immunotherapeutic modulation. Information

Substance Name: Amyloid Precursor Protein Secretases

Registry Number: EC 3.4.-

Grant and Affiliation Information for TgCRND8 amyloid precursor protein transgenic mice exhibit an altered gamma-secretase processing and an aggressive, additive amyloid pathology subject to immunotherapeutic modulation.

AFFILIATION: The Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, Sun City, Arizona 85351, USA.

Country: United States

AGENCY: United States NIA

GRANT: R01 AG 19795

ACRONYM: AG

MEDLINETA: Biochemistry

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