Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes

This study provides a comprehensive behavioral characterization during agin g of transgenic mice bearing,a both presenilin-1 (PS1) and amyloid precurso r protein (APP(670,671)) mutations. Doubly transgenic mice and non-transgen ic controls were evaluated at ages wherein beta -amyloid (A beta) neuropath ology in APP+PS1 mice is low (5-7 months) or very extensive (15-17 months). Progressive cognitive impairment was observed in transgenic mice for both water maze acquisition and radial arm water maze working memory. However, t ransgenicity did not affect Y-maze alternations, circular platform performa nce, standard water maze retention, or visible platform recognition at eith er age, nor did transgenicity affect anxiety levels in elevated plus-maze t esting. In sensorimotor tasks, transgenic mice showed a progressive increas e in open field activity, a progressive impairment in string agility, and a n early-onset impairment in balance: beam. None of these sensorimotor chang es appeared to be contributory to any cognitive impairments observed, howev er. Non-transgenic mice showed no progressive behavioral change in any meas ure evaluated. Given the age-related cognitive impairments presently observ ed in APP+PS1 transgenic mice and their progressive A beta deposition/neuro inflammation, A beta neuropathology could be involved in these progressive cognitive impairments. As such, the APP+PS1 transgenic mouse offers unique opportunities to develop therapeutics to treat or prevent Alzheimer's Disea se through modulation of A beta deposition/neuroinflammation. (C) 2001 Else vier Science B.V. All rights reserved.