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Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer’s disease


Year of Publication:
Contact PI Name:
Thomas A. Comery
Contact PI Affiliation:
Discovery Neuroscience Wyeth Research, Princeton, New Jersey, USA
Robert L. Martone, Suzan Aschmies, Kevin P. Atchison, George Diamantidis, Xiaohai Gong, Hua Zhou, Anthony F. Kreft, Menelas N. Pangalos, June Sonnenberg-Reines, J. Steven Jacobsen, Karen L. Marquis
Primary Reference (PubMED ID):
Funding Source:
Not Reported
Study Goal and Principal Findings:

The goal of this study was to determine if acute treatment with the gamma secretase inhibitor DAPT improved the impaired hippocampal function exhibited by young (20 weeks) and older (65 weeks) Tg2576 mice.  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), resulted in improved contextual memory in Tg2576 mice. At 20 weeks, a significant main effect of genotype (F(1,29) = 8.588; p < 0.05) was observed; however, neither the treatment main effect (F(1,29) = 1.213) nor the interaction (F(1,29) = 3.278) were significant. Vehicle-treated Tg2576 mice displayed no contextual conditioning and had memory scores significantly different from those observed in vehicle-treated controls (p< 0.05). In contrast, DAPT-treated (100 mg/kg) Tg2576 mice had memory scores that were not significantly different from those observed in the 20-week-old DAPT-treated controls (p = 0.4124) and displayed a significant increase relative to vehicle-treated Tg2576 mice (p < 0.05). In 36- and 54-week-old mice, significant group-by-treatment interactions were observed (36-week-old, F(1,28) = 5.751, p < 0.05; 54-week-old, F(1,26) = 4.465, p < 0.05). At both ages, DAPT-treated Tg2576 mice displayed significantly greater contextual memory than vehicle-treated Tg2576 mice (p < 0.05) and were not significantly different from DAPT-treated controls. In 65-week-old mice, as a result of animal availability, vehicle-treated Tg2576 were not tested. No significant difference was observed between control and Tg2576 mice treated with DAPT (F(1,18) = 1.212). No effect of DAPT was observed in controls at any age. An oral dose of 100 mg/kg of DAPT in Tg2576 mice resulted in reductions in brain levels of Aβ40 (F(6,48) = 10.912; p < 0.0001) and Aβ42 (F(6,48) = 3.706; p < 0.005). Significant reductions were observed in Aβ40 1–8 h and Aβ42 4–8 h after dosing relative to vehicle-treated Tg2576 mice. Levels of Aβ were no longer reduced 24 h after drug administration. These data support a role of β-amyloid in the hippocampal impairment in Tg2576 mic and, suggest that acute treatment with GSI may provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease.


Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Phosphodiesterase Type 4 (PDE4)
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
gamma Secretase

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Contextual Fear Conditioning
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Target Engagement (Reduction beta Amyloid Peptide 40-Brain)
Target Engagement (Reduction beta Amyloid Peptide 42-Brain)