TRANSGENIC MICE EXPRESSING APP-C100 IN THE BRAIN

The classic hallmarks of Alzheimer's disease are the deposition of amy loid in plaques and in the cerebrovasculature, and the emergence of ne urofibrillary tangles in neurons. The interplay between these two path ologic processes, on the one hand, and the degeneration of neurons and loss of cognitive functions on the other, remains incompletely unders tood. We have proposed that one crucial component of this interplay is a fragment of the Alzheimer amyloid protein precursor (APP) comprisin g the carboxyterminal 100 amino acids of this molecule, which we term APP-C100 (or, more simply, C100). This fragment, which comprises the 4 2-amino acid amyloid protein (AP) and an additional 58 amino acids car boxyterminal to it, was found to be toxic specifically to nerve cells in vitro. We developed transgenic mouse models to test the hypothesis that APP-C100 causes Alzheimer's disease neuropathology. APP-C100 was delivered to the mouse brain via a transgene expressing C100 under the control of the dystrophin brain promoter. These transgenic animal mod els for the action of APP-C100 in the brain exhibited some of the neur opathological features characteristic of Alzheimer disease brain. The animal models that we have created can be used to test hypotheses conc erning the mechanism by which C100 interacts with a neuronal receptor to kill neurons.