title: The γ-secretase modulator CHF5074 restores memory and hippocampal synaptic plasticity in plaque-free Tg2576 mice.
abstract: Abnormal amyloid-β (Aβ) production and deposition is believed to represent one of the main causes of Alzheimer's disease (AD). γ-Secretase is the enzymatic complex responsible for Aβ generation from its precursor protein. Inhibition or modulation of γ-secretase represents an attractive therapeutic approach. CHF5074 is a new γ-secretase modulator that has been shown to inhibit brain plaque deposition and to attenuate memory deficit in adult AD transgenic mice after chronic treatment. To date, it is not known whether the positive behavioral effects of this compound also occur in young transgenic mice without plaque deposition. Here, we evaluated the effects of acute and subchronic treatment with CHF5074 on contextual and recognition memory and on hippocampal synaptic plasticity in plaque-free Tg2576 mice. We found that at 5 months of age, contextual memory impairment was significantly attenuated after acute subcutaneous administration of 30 mg/kg CHF5074. At 6 months of age, recognition memory impairment was fully reversed after a 4-week oral treatment in the diet (≈60 mg/kg/day). These cognitive effects were associated with a reversal of long-term potentiation (LTP) impairment in the hippocampus. A significant reduction in brain intraneuronal AβPP/Aβ levels and hyperphosphorylated tau, but no change in soluble or oligomeric Aβ levels was detected in Tg2576 mice showing functional recovery following CHF5074 treatment. We conclude that the beneficial effects of CHF5074 treatment in young transgenic mice occurred at a stage that precedes plaque formation and were associated with a reduction in intraneuronal AβPP/Aβ and hyperphosphorylated tau.
authors.affiliation: Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Balducci
authors.forename: Bisan
authors.initials: B
authors.lastname: Mehdawy
authors.forename: Lydia
authors.initials: L
authors.lastname: Mare
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giuliani
authors.forename: Luca
authors.initials: L
authors.lastname: Lorenzini
authors.forename: Sandra
authors.initials: S
authors.lastname: Sivilia
authors.forename: Luciana
authors.initials: L
authors.lastname: Giardino
authors.forename: Laura
authors.initials: L
authors.lastname: Calzà
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: Pizzi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
authors.forename: Arturo R
authors.initials: AR
authors.lastname: Viscomi
authors.forename: Simone
authors.initials: S
authors.lastname: Ottonello
authors.forename: Gino
authors.initials: G
authors.lastname: Villetti
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Imbimbo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nisticò
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D006224:Cricetinae; D003521:Cyclopropanes / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D058225:Plaque, Amyloid; D013569:Synapses / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics
chemical_list: C522246:1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; D003521:Cyclopropanes; D005480:Flurbiprofen; D053829:Amyloid Precursor Protein Secretases