The γ-Secretase Modulator CHF5074 Restores Memory and Hippocampal Synaptic Plasticity in Plaque-Free Tg2576 Mice
| Autor: | Marina Pizzi, Claudia Balducci, Luciana Giardino, Alessandro Usiello, Arturo R. Viscomi, Gino Villetti, Giuseppe Nisticò, Bruno P. Imbimbo, Annamaria Lanzillotta, Gianluigi Forloni, Luca Lorenzini, Alessandro Giuliani, Ilenia Sarnico, Lydia Mare, Simone Ottonello, Sandra Sivilia, Laura Calzà, Bisan Mehdawy, Robert Nisticò |
|---|---|
| Přispěvatelé: | Balducci, C, Mehdawy, B, Mare, L, Giuliani, A, Lorenzini, L, Sivilia, S, Giardino, L, Calzà, L, Lanzillotta, A, Sarnico, I, Pizzi, M, Usiello, Alessandro, Viscomi, Ar, Ottonello, S, Villetti, G, Imbimbo, Bp, Nisticò, G, Forloni, G, Nisticò, R., C. Balducci, B. Mehdawy, L. Mare, A. Giuliani, L. Lorenzini, S. Sivilia, L. Giardino, L. Calzà, A. Lanzillotta, I. Sarnico, M. Pizzi, A. Usiello, A.R. Viscomi, S. Ottonello, G. Villetti, B.P. Imbimbo, G. Nisticò, G. Forloni and R. Nisticò |
| Rok vydání: | 2011 |
| Předmět: |
Cyclopropanes
Hippocampus Plaque Amyloid drug effects/genetics/physiology drug effects/enzymology/physiology Pharmacology Inbred C57BL Transgenic Mice Cricetinae Medicine Fear conditioning Amyloid Precursor Protein Secretases Animals Female Flurbiprofen Humans Memory Memory Disorders Mice Inbred C57BL Mice Transgenic Neuronal Plasticity Synapses Plaque chemistry.chemical_classification General Neuroscience Settore BIO/14 Long-term potentiation General Medicine Alzheimer's disease Psychiatry and Mental health Clinical Psychology antagonists /&/ inhibitors/genetics/metabolism/physiology Animals Cricetinae Cyclopropanes pharmacology/therapeutic use Female Flurbiprofen analogs /&/ derivatives/pharmacology/therapeutic use Hippocampus drug effects/enzymology/physiology Humans Memory Disorders drug therapy/enzymology/genetics Memory drug effects/physiology Mice Mice Inbred C57BL Mice Transgenic Neuronal Plasticity drug effects/genetics/physiology Plaque Amyloid Synapses drug effects/enzymology/genetics LTP analogs /&/ derivatives/pharmacology/therapeutic use Genetically modified mouse Amyloid Transgene drug therapy/enzymology/genetics amyloid-β pharmacology/therapeutic use gamma secretase modulator Recognition memory business.industry antagonists /&/ inhibitors/genetics/metabolism/physiology fear conditioning drug effects/physiology Enzyme chemistry Geriatrics and Gerontology business |
| Zdroj: | Journal of Alzheimer's Disease. 24:799-816 |
| ISSN: | 1875-8908 1387-2877 |
| DOI: | 10.3233/jad-2011-101839 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|