Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease.
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 beta-amyloid. Acute treatment before training (but not after training or before testing) with the gamma-secretase inhibitor (GSI) N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine-t-butylester (DAPT), at a dose that reduces brain concentrations of beta-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 beta-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.
Comery
Thomas A
TA
Discovery Neuroscience, Wyeth Research, CN8000, Princeton, New Jersey 08543, USA. comeryt@wyeth.com
Martone
Robert L
RL
Aschmies
Suzan
S
Atchison
Kevin P
KP
Diamantidis
George
G
Gong
Xiaohai
X
Zhou
Hua
H
Kreft
Anthony F
AF
Pangalos
Menelas N
MN
Sonnenberg-Reines
June
J
Jacobsen
J Steven
JS
Marquis
Karen L
KL
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000375:Aging / Q000523:psychology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000523:psychology*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000523:psychology; D003213:Conditioning, Psychological / Q000187:drug effects*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005239:Fear; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology; D014280:Triglycerides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D014280:Triglycerides; D005680:gamma-Aminobutyric Acid; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D020889:Rolipram