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 i s accompanied by neuropathology that includes the degeneration of neurons a nd the deposition of amyloid in plaques and in the cerebrovasculature. We h ave proposed that a fragment of the Alzheimer amyloid precursor protein (AP P) comprising the carboxyl-terminal 100 amino acids of this molecule (APP-C 100) plays a crucial role in the neurodegeneration and subsequent cognitive decline in AD. To test this hypothesis, we performed behavioral analyses o n transgenic mice expressing APP-C100 in the brain. The results revealed th at homozygous APP-C100 transgenic mice were significantly impaired in cued, spatial and reversal performance of a Morris water maze task, that the deg ree of the impairment in the spatial learning was age-dependent, and that t he 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 the ir spatial learning than were males. These findings show that expression of APP-C100 in the brain can cause age-dependent cognitive impairments that a re accompanied by hippocampal degeneration. (C) 1999 Elsevier Science B.V. All rights reserved.