QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

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

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (49) Citing Articles via Google Scholar Google Scholar Articles by Comery, T. A. Articles by Marquis, K. L. Search for Related Content PubMed PubMed Citation Articles by Comery, T. A. Articles by Marquis, K. L.

 Previous Article  |  Next Article 

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

---

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

This article has been cited by other articles:

				R. L. Martone, H. Zhou, K. Atchison, T. Comery, J. Z. Xu, X. Huang, X. Gong, M. Jin, A. Kreft, B. Harrison, et al. Begacestat (GSI-953): A Novel, Selective Thiophene Sulfonamide Inhibitor of Amyloid Precursor Protein {gamma}-Secretase for the Treatment of Alzheimer's Disease J. Pharmacol. Exp. Ther., November 1, 2009; 331(2): 598 - 608. [Abstract] [Full Text] [PDF]

				T. Bittner, M. Fuhrmann, S. Burgold, C. K. E. Jung, C. Volbracht, H. Steiner, G. Mitteregger, H. A. Kretzschmar, C. Haass, and J. Herms {gamma}-Secretase Inhibition Reduces Spine Density In Vivo via an Amyloid Precursor Protein-Dependent Pathway J. Neurosci., August 19, 2009; 29(33): 10405 - 10409. [Abstract] [Full Text] [PDF]

				D. Abramowski, K.-H. Wiederhold, U. Furrer, A.-L. Jaton, A. Neuenschwander, M.-J. Runser, S. Danner, J. Reichwald, D. Ammaturo, D. Staab, et al. Dynamics of A{beta} Turnover and Deposition in Different {beta}-Amyloid Precursor Protein Transgenic Mouse Models Following {gamma}-Secretase Inhibition J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 411 - 424. [Abstract] [Full Text] [PDF]

				J. S. Jacobsen, T. A. Comery, R. L. Martone, H. Elokdah, D. L. Crandall, A. Oganesian, S. Aschmies, Y. Kirksey, C. Gonzales, J. Xu, et al. Enhanced clearance of A{beta} in brain by sustaining the plasmin proteolysis cascade PNAS, June 24, 2008; 105(25): 8754 - 8759. [Abstract] [Full Text] [PDF]

				D. T. Teachey, A. E. Seif, V. I. Brown, M. Bruno, R. M. Bunte, Y. J. Chang, J. K. Choi, J. D. Fish, J. Hall, G. S. Reid, et al. Targeting Notch signaling in autoimmune and lymphoproliferative disease Blood, January 15, 2008; 111(2): 705 - 714. [Abstract] [Full Text] [PDF]

				G. Chen, K. S. Chen, D. Kobayashi, R. Barbour, R. Motter, D. Games, S. J. Martin, and R. G. M. Morris Active {beta}-Amyloid Immunization Restores Spatial Learning in PDAPP Mice Displaying Very Low Levels of {beta}-Amyloid J. Neurosci., March 7, 2007; 27(10): 2654 - 2662. [Abstract] [Full Text] [PDF]

				C. L. Masters and K. Beyreuther Alzheimer's centennial legacy: prospects for rational therapeutic intervention targeting the A{beta} amyloid pathway Brain, November 1, 2006; 129(11): 2823 - 2839. [Abstract] [Full Text] [PDF]

				J. S. Jacobsen, C.-C. Wu, J. M. Redwine, T. A. Comery, R. Arias, M. Bowlby, R. Martone, J. H. Morrison, M. N. Pangalos, P. H. Reinhart, et al. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease PNAS, March 28, 2006; 103(13): 5161 - 5166. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help