Age-Related Changes in Cognitive, Emotional, and Motor Behaviour in Male and Female 3xTg-AD Mice: A Longitudinal Study

Abstract

The 3xTg-AD mouse model of Alzheimer’s disease has three transgenes (APPswe, PS1M146V, and Tau P301L) that cause the development of amyloid beta plaques, neurofibrillary tangles, and cognitive deficits. The breeding system of the 3xTg-AD mice requires that the transgenic mice be reared by transgenic mothers and the wildtype controls (B6129SF2) reared by wildtype mothers. To assess the effect of maternal genotype we cross-fostered pups to create mixed genotype litters and tested pups in a longitudinal study from 2 to 18 months of age. We found little evidence of a lasting effect of maternal genotype on behaviour or neuropathology. The 3xTg-AD mice had enhanced motor abilities on Rotarod and decreased anxiety-like behaviour from 2 to 18 months of age. We found no deficits in social behaviour at any age tested. The 3xTg-AD mice had a deficit in spatial learning and memory in the MWM from 2 – 18 months of age. To further characterize the motor phenotype we performed an extensive motor test battery at six months of age and found the 3xTg-AD mice had enhanced motor performance on the Rotarod, but worse performance on the grid suspension task. The 3xTg-AD mice had a longer stride length in gait analysis and made more foot slips on the balance beam than wildtype mice. There was no difference in voluntary wheel-running activity between genotypes, but there was a disruption in circadian activity rhythm in 3xTg-AD mice. We then tested mice at 6.5 months of age on a series of cognitive tasks to determine which was the most sensitive to detect cognitive deficits. We found that the Barnes maze was the most sensitive; the 3xTg-AD mice had impaired learning and memory in the Barnes maze but performed better than B6129SF2 wildtype mice in the Y-Maze and in contextual fear conditioning. Neither genotype demonstrated a preference in novel object recognition nor was there a genotype difference in cued fear conditioning. Overall the 3xTg-AD mouse develops some of the deficits that would be expected of a mouse model of Alzheimer’s disease but has fairly mild cognitive deficits even at 18 months of age.