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Acute γ-Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's Disease
- Source :
- The Journal of Neuroscience. 25:8898-8902
- Publication Year :
- 2005
- Publisher :
- Society for Neuroscience, 2005.
-
Abstract
- Transgenic mice (Tg2576) overexpressing the Swedish mutation of the human amyloid precursor protein display biochemical, pathological, and behavioral markers consistent with many aspects of Alzheimer's disease, including impaired hippocampal function. Impaired, hippocampal-dependent, contextual fear conditioning (CFC) is observed in mice as young as 20 weeks of age. This impairment can be attenuated after treatment before training with the phosphodiesterase-4 inhibitor rolipram (0.1 mg/kg, i.p.). A rolipram-associated improvement is also observed in the littermate controls, suggesting that the effect of rolipram is independent of β-amyloid. Acute treatment before training (but not after training or before testing) with the γ-secretase inhibitor (GSI)N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine-t-butylester (DAPT), at a dose that reduces brain concentrations of β-amyloid (100 mg/kg), attenuates the impairment in 20- to 65-week-old Tg2576 mice. Importantly, DAPT had no effect on performance of control littermates. These data are supportive of a role of β-amyloid in the impairment of CFC in Tg2576 mice. Furthermore, they suggest that acute treatment with GSI may provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease.
- Subjects :
- Genetically modified mouse
Aging
medicine.medical_specialty
Amyloid
Phosphodiesterase Inhibitors
Transgene
Mice, Transgenic
Amyloid beta-Protein Precursor
Mice
Cognition
Alzheimer Disease
Internal medicine
Conditioning, Psychological
Endopeptidases
medicine
Amyloid precursor protein
Animals
Aspartic Acid Endopeptidases
Dementia
Enzyme Inhibitors
Pathological
Triglycerides
gamma-Aminobutyric Acid
Rolipram
Amyloid beta-Peptides
biology
General Neuroscience
Fear
medicine.disease
Cyclic Nucleotide Phosphodiesterases, Type 4
Disease Models, Animal
Endocrinology
3',5'-Cyclic-AMP Phosphodiesterases
Mutation
biology.protein
Amyloid Precursor Protein Secretases
Brief Communications
Cognition Disorders
Psychology
Neuroscience
Amyloid precursor protein secretase
medicine.drug
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....44b492d9ca4d6361b6a9a861cd42e865