title: 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 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.
authors.affiliation: Amylgen, Clapiers, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Meunier
authors.forename: Vanessa
authors.initials: V
authors.lastname: Villard
authors.forename: Laurent
authors.initials: L
authors.lastname: Givalois
authors.forename: Tangui
authors.initials: T
authors.lastname: Maurice
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000494:pharmacology*; D000818:Animals; D002087:Butyrates / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
chemical_list: C497115:4-(2-((1R)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid; D016229:Amyloid beta-Peptides; D002087:Butyrates; D006846:Hydrocarbons, Halogenated; D010446:Peptide Fragments; D011480:Protease Inhibitors; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D053829:Amyloid Precursor Protein Secretases