We investigated the morphology and biochemistry of the amyloid-
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(A
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) 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 A
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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 A
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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 A
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load. A
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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 A
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chemistry between Tg mice and AD, caution should be appliedin projecting mouse therapeutic interventions onto human subjects.