title: Amelioration of cognitive deficits in plaque-bearing Alzheimer's disease model mice through selective reduction of nascent soluble Aβ42 without affecting other Aβ pools.
abstract: Given that amyloid-β 42 (Aβ42) is believed to be a culprit in Alzheimer's disease (AD), reducing Aβ42 production should be a potential therapeutic approach. γ-Secretase modulators (GSMs) cause selective reduction of Aβ42 or both reduction of Aβ42 and Aβ40 without affecting total Aβ through shifting the γ-cleavage position in amyloid precursor protein. We recently reported on GSM-2, one of the second-generation GSMs, that selectively reduced brain Aβ42 level and significantly ameliorated cognitive deficits in plaque-free 5.5-month-old Tg2576 AD model mice. Here, we investigated the effects of GSM-2 on 10-, 14-, and 18-month-old mice which had age-dependent increase in amyloid plaques. Eight-day treatment with GSM-2 significantly ameliorated cognitive deficits measured by Y-maze task in the mice of any age. However, GSM-2 reduced brain soluble Aβ42 only in 10-month-old mice. In contrast, GSM-2 markedly reduced newly synthesized soluble Aβ42 in both 10- and 18-month-old mice with similar efficacy when measured using the stable isotope-labeling technique, suggesting that nascent Aβ42 plays a more significant role than plaque-associated soluble Aβ42 in the cognitive deterioration of Tg2576 mice. These findings further indicate the potential utility of approach to reducing Aβ42 synthesis in AD therapeutic regimens.
authors.affiliation: Pharmacology Research Labs, Astellas Pharma Inc, Tsukuba, Ibaraki, Japan. yasuyuki.mitani@astellas.com
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Mitani
authors.forename: Junko
authors.initials: J
authors.lastname: Yarimizu
authors.forename: Hiroki
authors.initials: H
authors.lastname: Akashiba
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Shitaka
authors.forename: Keni
authors.initials: K
authors.lastname: Ni
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
mesh_terms: D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use; D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D002853:Chromatography, Liquid; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C581775:1-((1,1,1-trifluoro-7-methyloctan-4-yl)-2-(4-(trifluoromethyl)phenyl)piperidin-4-yl)acetic acid; D000085:Acetates; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D010880:Piperidines; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases