The γ-secretase inhibitor 2-[(1R)-1-[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl) amino]ethyl-5-fluorobenzenebutanoic acid (BMS-299897) alleviates Aβ1–42 seeding and short-term memory deficits in the Aβ25–35 mouse model of Alzheimer's disease

Abstract

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-β fragment Aβ25–35. It was recently reported that Aβ25–35 also provokes a modification of APP processing with accumulation of endogenous Aβ1–42. We here analyzed whether a γ-secretase inhibitor, BMS-299897, attenuated this Aβ25–35-induced Aβ1–42 seeding and toxicity. The compound was administered at 0.1–1nmol/mouse, concomittantly with Aβ25–35 (9nmol) in male Swiss mice. After one week, the contents in Aβ1–42 and Aβ1–40, 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. Aβ25–35 increased Aβ1–42 content (+240%) but failed to affect Aβ1–40. BMS-299897 blocked the increase in Aβ1–42 content and decreased Aβ1–40 levels significantly. The compound did not affect Aβ25–35-induced increase in hippocampal lipid peroxidation. Behaviorally, BMS-299897 blocked the Aβ25–35-induced deficits in spontaneous alternation or novel object recognition, using a 1h intertrial time interval. BMS-299896 failed to affect the passive avoidance impairments or novel object recognition, using a 24h intertrial time interval. These results confirmed that Aβ25–35 injection provoked an accumulation in endogenous Aβ1–42, an effect blocked by γ-secretase inhibition. This Aβ1–42 accumulation marginally contributed to the toxicity or long-term memory deficits. However, since the seeded Aβ1–42 affected short-term memory, the rapid Aβ25–35 injection Alzheimer's disease model could be used to screen the activity of new secretase inhibitors.