Reference and working memory deficits in the 3xTg-AD mouse between 2 and 15-months of age: A cross-sectional study

• Triple transgenic Alzheimer's (3xTg-AD) mice showed working and reference memory deficits at 2, 6, 12, and 15-months of age.
• These deficits are relatively stable across all ages tested (with the exception of 9-months of age) and do not increase with age.
• Male 3xTg-AD mice showed more working memory and reference memory deficits than female 3xTg-AD mice.
• Findings suggest genes responsible for working and reference memory cause deficits from an early age.
• Attention should be paid to sex differences in AD mouse models.

Impairments in working memory (WM) can predict the shift from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and the rate at which AD progresses with age. The 3xTg-AD mouse model develops both Aβ plaques and neurofibrillary tangles, the neuro-pathological hallmarks of AD, by 6 months of age, but no research has investigated the age-related changes in WM in these mice. Using a cross-sectional design, we tested male and female 3xTg-AD and wildtype control (B6129SF2/J) mice between 2 and 15 months of age for reference and working memory errors in the 8-arm radial maze. The 3xTg-AD mice had deficits in both working and reference memory across the ages tested, rather than showing the predicted age-related memory deficits. Male 3xTg-AD mice showed more working and reference memory errors than females, but there were no sex differences in wildtype control mice. These results indicate that the 3xTg-AD mouse replicates the impairments in WM found in patients with AD. However, these mice show memory deficits as early as two months of age, suggesting that the genes underlying reference and working memory in these mice cause deficits from an early age. The finding that males were affected more than females suggests that more attention should be paid to sex differences in transgenic AD mice.