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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.

 


Authors :  
Meunier J1, Villard V, Givalois L, Maurice T

 


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 Aβ(25-35). It was recently reported that Aβ(25-35) also provokes a modification of APP processing with accumulation of endogenous Aβ(1-42). We here analyzed whether a γ-secretase inhibitor, BMS-299897, attenuated this Aβ(25-35)-induced Aβ(1-42) seeding and toxicity. The compound was administered at 0.1-1 nmol/mouse, concomittantly with Aβ(25-35) (9 nmol) in male Swiss mice. After one week, the contents in Aβ(1-42) and Aβ(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. Aβ(25-35) increased Aβ(1-42) content (+240%) but failed to affect Aβ(1-40). BMS-299897 blocked the increase in Aβ(1-42) content and decreased Aβ(1-40) levels significantly. The compound did not affect Aβ(25-35)-induced increase in hippocampal lipid peroxidation. Behaviorally, BMS-299897 blocked the Aβ(25-35)-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 Aβ(25-35) injection provoked an accumulation in endogenous Aβ(1-42), an effect blocked by γ-secretase inhibition. This Aβ(1-42) accumulation marginally contributed to the toxicity or long-term memory deficits. However, since the seeded Aβ(1-42) affected short-term memory, the rapid Aβ(25-35) injection Alzheimer’s disease model could be used to screen the activity of new secretase inhibitors.

Copyright © 2012 Elsevier B.V. All rights reserved.

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