Résumé
Alzheimer's disease pathomimetic toxicity could be induced in mice within one week after the intracerebroventricular (i.c.v.) injection of an aggregated preparation of the highly toxic and endogenous amyloid-[beta] fragment A[beta]25a35. It was recently reported that A[beta]25a35 also provokes a modification of APP processing with accumulation of endogenous A[beta]1a42. We here analyzed whether a [gamma]-secretase inhibitor, BMS-299897, attenuated this A[beta]25a35-induced A[beta]1a42 seeding and toxicity. The compound was administered at 0.1a1 nmol/mouse, concomittantly with A[beta]25a35 (9 nmol) in male Swiss mice. After one week, the contents in A[beta]1a42 and A[beta]1a40, and the levels in lipid peroxidation were analyzed in the mouse hippocampus. Mice were submitted to spontaneous alternation, passive avoidance and object recognition to analyze their short- and long-term memory abilities. A[beta]25a35 increased A[beta]1a42 content (+240%) but failed to affect A[beta]1a40. BMS-299897 blocked the increase in A[beta]1a42 content and decreased A[beta]1a40 levels significantly. The compound did not affect A[beta]25a35-induced increase in hippocampal lipid peroxidation. Behaviorally, BMS-299897 blocked the A[beta]25a35-induced deficits in spontaneous alternation or novel object recognition, using a 1 h intertrial time interval. BMS-299896 failed to affect the passive avoidance impairments or novel object recognition, using a 24 h intertrial time interval. These results confirmed that A[beta]25a35 injection provoked an accumulation in endogenous A[beta]1a42, an effect blocked by [gamma]-secretase inhibition. This A[beta]1a42 accumulation marginally contributed to the toxicity or long-term memory deficits. However, since the seeded A[beta]1a42 affected short-term memory, the rapid A[beta]25a35 injection Alzheimer's disease model could be used to screen the activity of new secretase inhibitors.