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

摘要: Aging of transgenic mice that overexpress the London mutant amyloid precursor protein (APP/V717I) (Moechars et al., 1999a) was now demonstrated not to affect normalized levels aor b-cleaved secreted APP nor b-C-terminal stubs. This indicated aging did markedly disturb either a -o r b-secretase cleavage and failed explain origin massive amounts peptides Ab40 Ab42, soluble precipitated as plaques in brain old APP/V717I mice. We tested hypothesis acted on presenilin1 (PS1) g-secretase-mediated production by comparing aged double coexpressing human PS1 APP/V717I. In with (A246E) but wild-type PS1, peptide increased resulted when were only 6‐9 months old, much earlier than (12‐15 old). Mutant mainly Ab42 levels, whereas mice, both increased. dramatic difference Ab42/Ab40 ratio or plaqueassociated peptides, i.e., 3.11 6 0.22 APP/ V717I 3 PS1/A246E compared 0.43 0.07 clear between effect insertion transgene. conclusion, we demonstrate favor amyloidogenic over nonamyloidogenic processing APP, it exert PS1-like g-secretase. Therefore, data are interpreted suggest parenchymal vascular accumulation from failure rather production.