The ¦Ã-secretase inhibitor 2-[(1R)-1-[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl) amino]ethyl-5-fluorobenzenebutanoic acid (BMS-299897) alleviates A¦Â_1-42 seeding and short-term memory deficits in the A¦Â_25-35 mouse model of Alzhei

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• 作者：Johann Meunier^a ; Vanessa Villard^a ; Laurent Givalois^b ; ^c ; ^d ; Tangui Maurice^b ; ^c ; ^d ; ^{maurice@univ-montp2.fr}
• 关键词：Alzheimer's disease ; Amyloid-¦Â peptide ; ¦Ã-secretase inhibitor ; Amyloid protein seeding ; Drug discovery
• 刊名：European Journal of Pharmacology
• 出版年：2013
• 出版时间：5 January, 2013
• 年：2013
• 卷：698
• 期：1-3
• 页码：193-199
• 全文大小：587 K

文摘

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-¦Â fragment A¦Â_25-35. It was recently reported that A¦Â_25-35 also provokes a modification of APP processing with accumulation of endogenous A¦Â_1-42. We here analyzed whether a ¦Ã-secretase inhibitor, BMS-299897, attenuated this A¦Â_25-35-induced A¦Â_1-42 seeding and toxicity. The compound was administered at 0.1-1 nmol/mouse, concomittantly with A¦Â_25-35 (9 nmol) in male Swiss mice. After one week, the contents in A¦Â_1-42 and A¦Â_1-40, 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. A¦Â_25-35 increased A¦Â_1-42 content (+240 % ) but failed to affect A¦Â_1-40. BMS-299897 blocked the increase in A¦Â_1-42 content and decreased A¦Â_1-40 levels significantly. The compound did not affect A¦Â_25-35-induced increase in hippocampal lipid peroxidation. Behaviorally, BMS-299897 blocked the A¦Â_25-35-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¦Â_25-35 injection provoked an accumulation in endogenous A¦Â_1-42, an effect blocked by ¦Ã-secretase inhibition. This A¦Â_1-42 accumulation marginally contributed to the toxicity or long-term memory deficits. However, since the seeded A¦Â_1-42 affected short-term memory, the rapid A¦Â_25-35 injection Alzheimer's disease model could be used to screen the activity of new secretase inhibitors.