Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein

In Alzheimer's disease (AD), a progressive decline of cognitive functions is accompanied by neuropathology that includes the degeneration of neurons and the deposition of amyloid in plaques and in the cerebrovasculature. We have proposed that a fragment of the Alzheimer amyloid precursor protein (APP) comprising the carboxyl-terminal 100 amino acids of this molecule (APP-C100) plays a crucial role in the neurodegeneration and subsequent cognitive decline in AD. To test this hypothesis, we performed behavioral analyses on transgenic mice expressing APP-C100 in the brain. The results revealed that homozygous APP-C100 transgenic mice were significantly impaired in cued, spatial and reversal performance of a Morris water maze task, that the degree of the impairment in the spatial learning was age-dependent, and that the homozygous mice displayed significantly more degeneration of neurons in Ammon's horn of the hippocampal formation than did heterozygous or control mice. Among the heterozygotes, females were relatively more impaired in their spatial learning than were males. These findings show that expression of APP-C100 in the brain can cause age-dependent cognitive impairments that are accompanied by hippocampal degeneration. (C) 1999 Elsevier Science B.V. All rights reserved.