Aging Increased Amyloid Peptide and Caused Amyloid Plaques in Brain of Old APP/V717I Transgenic Mice by a Different Mechanism than Mutant Presenilin1

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Abstract
Aging of transgenic mice that overexpress the London mutant of amyloid precursor protein (APP/V717I) (Moechars et al., 1999a) was now demonstrated not to affect the normalized levels of α- or β-cleaved secreted APP nor of the β-C-terminal stubs. This indicated that aging did not markedly disturb either α- or β-secretase cleavage of APP and failed to explain the origin of the massive amounts of amyloid peptides Aβ40 and Aβ42, soluble and precipitated as amyloid plaques in the brain of old APP/V717I transgenic mice. We tested the hypothesis that aging acted on presenilin1 (PS1) to affect γ-secretase-mediated production of amyloid peptides by comparing aged APP/V717I transgenic mice to double transgenic mice coexpressing human PS1 and APP/V717I. In double transgenic mice with mutant (A246E) but not wild-type human PS1, brain amyloid peptide levels increased and resulted in amyloid plaques when the mice were only 6–9 months old, much earlier than in APP/V717I transgenic mice (12–15 months old). Mutant PS1 increased mainly brain Aβ42 levels, whereas in aged APP/V717I transgenic mice, both Aβ42 and Aβ40 increased. This resulted in a dramatic difference in the Aβ42/Aβ40 ratio of precipitated or plaque-associated amyloid peptides, i.e., 3.11 ± 0.22 in double APP/V717I × PS1/A246E transgenic mice compared with 0.43 ± 0.07 in aged APP/V717I transgenic mice, and demonstrated a clear difference between the effect of aging and the effect of the insertion of a mutant PS1 transgene. In conclusion, we demonstrate that aging did not favor amyloidogenic over nonamyloidogenic processing of APP, nor did it exert a mutant PS1-like effect on γ-secretase. Therefore, the data are interpreted to suggest that parenchymal and vascular accumulation of amyloid in aging brain resulted from failure to clear the amyloid peptides rather than from increased production.