ABSTRACT
Title
Oral treatment with the novel γ-secretase modulator CHF5074 attenuates synaptic dysfunction and reduces tau phosphorylation in young, plaque-free Tg2576 mice
Authors
R. Nisticò1, M. Pizzi2, B. P. Imbimbo3
1Department of Pharmacobiology, University of Calabria,87036 Rende, Italy
2 Department of Biomedical Sciences and Biotechnologies, University of Brescia
3Research and Development Department, Chiesi Farmaceutici, Parma, Italy
1Department of Pharmacobiology, University of Calabria,87036 Rende, Italy
2 Department of Biomedical Sciences and Biotechnologies, University of Brescia
3Research and Development Department, Chiesi Farmaceutici, Parma, Italy
Abstract
Abnormal β -amyloid (Aβ) production and deposition is believed to represent one of the main cause of Alzheimer’s disease (AD). γ-Secretase is the enzyme complex responsible for Aβ generation from its precursor protein (Wolfe, 2006). Thus, inhibition or modulation of γ-secretase represents nowadays an attractive therapeutic approach. Transgenic mice that express human disease variants of APP or presenilin 1 develop amyloid plaques, memory impairment, deficits in synaptic function, gliosis, and dystrophic neurites (Morrissette et al., 2009). CHF5074 is a new γ-secretase modulator that has been shown to inhibit brain plaque deposition and attenuate memory deficit in adult AD transgenic mice after chronic treatment (Imbimbo et al., 2009). It is not known whether the positive behavioral effects of the drug are directly linked to an action on plaque deposition. Here we report normal basal synaptic activity and impairment of hippocampal long-term potentiation (LTP) in 6-months old Tg2576 mice, before plaque deposition. Interestingly, Tg2576 mice treated with oral CHF5074, showed a significant improvement in synaptic plasticity, and this effect was correlated with a reduction in tau phosphorylation without change in soluble or oligomeric Ablevels. We conclude that the beneficial effects of subchronic treatment with CHF5074 in young, plaque-free transgenic mice suggest that the action of CHF5074 could be independent from an effect on Aβ deposition.
References
Imbimbo BP, Hutter-Paier B, Villetti G, Facchinetti F, Cenacchi V, Volta R, Lanzillotta A, Pizzi M, Windisch M. CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease. Br J Pharmacol. 2009 Mar;156(6):982-93.
Morrissette DA, Parachikova A, Green KN, LaFerla FM. Relevance of transgenic mouse models to human Alzheimer disease. J Biol Chem. 2009 Mar 6;284(10):6033-7.
Wolfe MS. The gamma-secretase complex: membrane-embedded proteolytic ensemble. Biochemistry. 2006 Jul 4;45(26):7931-9.
References
Imbimbo BP, Hutter-Paier B, Villetti G, Facchinetti F, Cenacchi V, Volta R, Lanzillotta A, Pizzi M, Windisch M. CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease. Br J Pharmacol. 2009 Mar;156(6):982-93.
Morrissette DA, Parachikova A, Green KN, LaFerla FM. Relevance of transgenic mouse models to human Alzheimer disease. J Biol Chem. 2009 Mar 6;284(10):6033-7.
Wolfe MS. The gamma-secretase complex: membrane-embedded proteolytic ensemble. Biochemistry. 2006 Jul 4;45(26):7931-9.