AGE-DEPENDENT NEURONAL AND SYNAPTIC DEGENERATION IN MICE TRANSGENIC FOR THE C-TERMINUS OF THE AMYLOID PRECURSOR PROTEIN

The molecular basis for the degeneration of neurons and the deposition of amyloid in plaques and in the cerebrovasculature in Alzheimer's di sease (AD) is incompletely understood. We have proposed that one molec ule common to these abnormal processes is a fragment of the Alzheimer amyloid precursor protein (APP) comprising the C-terminal 100 amino ac ids of this molecule (APP-C100). We tested this hypothesis by creating transgenic mice expressing APP-C100 in the brain, We report here that aging (18-28 month) APP-C100 transgenic mice exhibit profound degener ation of neurons and synapses in Ammon's horn and the den tate gyrus o f the hippocampal formation. Of the 106 transgenic mice between 8 and 28 months of age that were examined, all of those older than 18 months displayed severe hippocampal degeneration. The numerous degenerating axonal profiles contained increased numbers of neurofilaments, whorls of membrane, and accumulations of debris resembling secondary lysosome s near the cell body. The dendrites of degenerating granule and pyrami dal cells contained disorganized, wavy microtubules. Cerebral blood ve ssels had thickened refractile basal laminae, and microglia laden with debris lay adjacent to larger venous vessels. Mice transgenic for Fla g-APP-C100 (in which the hydrophilic Flag tag was fused to the N termi nus of APP-C100) showed a similar degree of neurodegeneration in the h ippocampal formation as early as 12 months of age, The 45 control mice displayed only occasional necrotic cells and no extensive cell degene ration in the same brain regions, These findings show that APP-C100 is capable of causing some of the neuropathological[ features of AD.