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The Journal of Neuroscience, September 28, 2005, 25(39):8898-8902; doi:10.1523/JNEUROSCI.2693-05.2005

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BRIEF COMMUNICATION
Acute -Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's Disease

Thomas A. Comery,¹ Robert L. Martone,¹ Suzan Aschmies,¹ Kevin P. Atchison,¹ George Diamantidis,² Xiaohai Gong,¹ Hua Zhou,¹ Anthony F. Kreft,² Menelas N. Pangalos,¹ June Sonnenberg-Reines,¹ J. Steven Jacobsen,¹ and Karen L. Marquis¹

¹Discovery Neuroscience and ²Chemical and Screening Sciences, Wyeth Research, CN8000, Princeton, New Jersey 08543

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 -amyloid. Acute treatment before training (but not after training or before testing) with the -secretase inhibitor (GSI) N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butylester (DAPT), at a dose that reduces brain concentrations of -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 -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.

Key words: Alzheimer's disease; amyloid; learning; memory; secretase; dementia

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Received Feb 18, 2005; revised June 30, 2005; accepted July 28, 2005.

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