Progressive and gender-dependent cognitive impairment in the APPSW transgenic mouse model for Alzheimer's disease

To determine if early cognitive/sensorimotor deficits exist in APP(sw) transgenic mice overexpressing human amyloid precursor protein (APP), Tg + and Tg- animals at both 3 and 9 months of age (3M and 9M, respectively) were evaluated in a comprehensive battery of measures. The performance of all Tg + mice at both ages was no different from all Tg - controls in Y-maze alternations, water maze acquisition, passive avoidance, and active avoidance testing. By contrast, results from other tasks revealed substantive cognitive deficits in Tg+ mice that were usually gender-dependent and sometimes progressive in nature. Between 3M and 9M, a progressive impairment was observed in circular platform performance by Tg+ males, as was a progressive deficit in visible platform testing for all Tg + animals. Other transgenic effects included both impaired water maze retention and circular platform performance in 3M Tg + females; this later effect was responsible for an overall (males + females) Tg + deficit in circular platform performance at 3M. Sensorimotor testing revealed several Tg+ effects, most notably an increased activity of Tg + males in both open field and Y-maze at 3M. Significant correlations between a number of behavioral measures were observed, although factor analysis suggests that each task measured components of sensorimotor/cognitive function not measured by other tasks. Finally, Tg + mice had lower survivability than Tg - animals through 9M (85 vs. 96%). In summary, these results demonstrate the presence of gender-related and progressive cognitive deficits in APP(sw) transgenic mice at a relatively early age (i.e., prior to overt, P-amyloid deposition in the brain), suggesting a pathophysiologic role for elevated levels of 'soluble' beta-amyloid in such impairments. (C) 1999 Elsevier Science B.V. All rights reserved.