Specific spatial learning deficits become severe with age in beta-amyloid precursor protein transgenic mice that harbor diffuse beta-amyloid depositsbut do not form plaques

Memory impairment progressing to dementia is the main clinical symptom of A lzheimer's disease (AD). AD is characterized histologically by the presence of beta -amyloid (A beta) plaques and neurofibrillary tangles in specific brain regions. Although A beta derived from the A beta precursor protein (b eta -APP) is believed to play a central etiological role in AD, it is not c lear whether soluble and/or fibrillar forms are responsible for the memory deficit. We have generated and previously described mice expressing human w ild-type beta -APP(751) isoform in neurons. These transgenic mice recapitul ate early histopathological features of AD and form A beta deposits but no plaques. Here we describe a specific and progressive learning and memory im pairment in these animals. In the Morris water maze, a spatial memory task sensitive to hippocampal damage, one pedigree already showed significant di fferences in acquisition in 3-month-old mice that increased in severity wit h age and were expressed clearly in 6-month- and 2-year-old animals. The se cond transgenic pedigree displayed a milder impairment with a later age of onset. Performance deficits significantly decreased during the 6 days of tr aining in young but not in aged transgenic animals. Both pedigrees of the t ransgenic mice differed from wild-type mice by less expressed increase of e scape latencies after the platform position had been changed in the reversa l experiment and by failure to prefer the goal quadrant in probe trials. Bo th pedigrees performed at wild-type level in a number of other tests (open field exploration and passive and active place avoidance). The results sugg est that plaque formation is not a necessary condition for the neuronal bet a -APP(751) transgene-induced memory impairment, which may be caused by bet a -APP overexpression, isoform misexpression, or elevated soluble A beta.