TgCRND8 amyloid precursor protein transgenic mice exhibit an altered gamma-secretase processing and an aggressive, additive amyloid pathology subject to immunotherapeutic modulation.
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.
Van Vickle
Gregory D
GD
The Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, Sun City, Arizona 85351, USA.
Esh
Chera L
CL
Kalback
Walter M
WM
Patton
R Lyle
RL
Luehrs
Dean C
DC
Kokjohn
Tyler A
TA
Fifield
Frederick G
FG
Fraser
Paul E
PE
Westaway
David
D
McLaurin
Joanne
J
Lopez
John
J
Brune
Daniel
D
Newel
Amanda J
AJ
Poston
Marissa
M
Beach
Thomas G
TG
Roher
Alex E
AE
D000544:Alzheimer Disease / Q000473:pathology* / Q000628:therapy*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000648:ultrastructure; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D007167:Immunotherapy; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D058225:Plaque, Amyloid / Q000473:pathology* / Q000648:ultrastructure; D011499:Protein Processing, Post-Translational; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013844:Thiazoles / Q000378:metabolism
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D052160:Benzothiazoles; D013844:Thiazoles; C009462:thioflavin T; D053829:Amyloid Precursor Protein Secretases