title: The γ-secretase modulator CHF5074 reduces the accumulation of native hyperphosphorylated tau in a transgenic mouse model of Alzheimer's disease.
abstract: The relationship between β-amyloid (Aβ) and tau is not fully understood, though it is proposed that in the pathogenesis of Alzheimer's disease (AD) Aβ accumulation precedes and promotes tau hyperphosphorylation via activation of glycogen synthase kinase-3beta (GSK-3β). Both events contribute to learning and memory impairments. Modulation of γ-secretase activity has proved to reduce the Aβ burden and cognitive deficits in mouse models of AD, but its ability in reducing the tau pathology remains elusive. Chronic treatments with two γ-secretase modulators, ibuprofen and CHF5074, disclosed higher activity of CHF5074 in ameliorating brain plaque deposition and spatial memory deficits in transgenic mice expressing human amyloid precursor protein (hAPP) with Swedish and London mutations (APP(SL) mice). The aim of our study was to investigate in APP(SL) mice the effect of the two compounds on the accumulation of native hyperphosphorylated tau as well as on the GSK-3β signaling. CHF5074 was more effective than ibuprofen in reducing tau pathology, though both compounds decreased the GSK-3β level and increased the GSK-3β inhibitory phosphorylation near to the non-Tg values. The inhibition of GSK-3β appeared to be secondary to the reduction of Aβ generation as, differently from LiCl, CHF5074 reproduced its effect in hAPP-overexpressing neuroglioma cells, but not in wild-type primary neurons. Our data show that the novel γ-secretase modulator CHF5074 can fully reverse β-amyloid-associated tau pathology, thus representing a promising therapeutic agent for AD.
authors.affiliation: Division of Pharmacology and Experimental Therapeutics, Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia and Istituto Nazionale di Neuroscienze Brescia, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Lanzillotta
authors.forename: Ilenia
authors.initials: I
authors.lastname: Sarnico
authors.forename: Marina
authors.initials: M
authors.lastname: Benarese
authors.forename: Caterina
authors.initials: C
authors.lastname: Branca
authors.forename: Cristina
authors.initials: C
authors.lastname: Baiguera
authors.forename: Birgit
authors.initials: B
authors.lastname: Hutter-Paier
authors.forename: Manfred
authors.initials: M
authors.lastname: Windisch
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Spano
authors.forename: Bruno Pietro
authors.initials: BP
authors.lastname: Imbimbo
authors.forename: Marina
authors.initials: M
authors.lastname: Pizzi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology*; D004032:Diet; D004195:Disease Models, Animal; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C522246:1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; D016229:Amyloid beta-Peptides; D016861:Cyclooxygenase Inhibitors; D003521:Cyclopropanes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D005480:Flurbiprofen; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D007052:Ibuprofen