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SAGE KE Bulletin Board

Highlights of the 34th Annual Meeting of the Society for Neuroscience 2004 in San Diego

4 November 2004

Dietmar R. Thal

Caspase cleavage of the C-terminal fragment is a critical event in amyloid beta-protein (Abeta) toxicity: Galvan et al. (Galvan et al. 2004) presented a mouse model carrying the APP mutation of the PDAPP mouse plus a D664A mutation. Caspase cleavage of APP at position 664 leads to the production of cytotoxic C-terminal fragments. The D664A mutation blocks this caspase cleavage and the cytotoxic C-terminal fragment can no longer be produced. The mice carrying this mutation produce Abeta plaques but do not show synaptic pathology and behavioral changes seen in PDAPP mice without the D664A mutation (Galvan et al. 2004; Schroeder et al. 2004). This model highlights the importance of the C-terminal fragment in Abeta-toxicity. However, it is well established that Abeta-immunization in PDAPP mice is also capable of saving the mouse from developing behavioral deficits and synaptic pathology (Lombardo et al. 2003). In so doing, both Abeta and the C-terminal fragment seem to be necessary for Abeta-toxicity. References Galvan, V., M. Saganich, et al. (2004). "Reversal of AD- like pathology in APP transgenic mice by mutation of ASP664." 2004 Abstract Viewer/Itinerary Planner: Program No. 488.4. Lombardo, J. A., E. A. Stern, et al. (2003). "Amyloid-beta antibody treatment leads to rapid normalization of plaque-induced neuritic alterations." J Neurosci 23(34): 10879-83. Schroeder, B. E., M. J. Saganich, et al. (2004). "The importance of caspase cleavage of the cytoplasmic domain of amyloid precursor protein (APP) in the behavioral and synaptic transmission deficits of APP transgenic mice." 2004 Abstract Viewer/Itinerary Planner: Program No. 488.5.

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