PLB2Tau mice are impaired in novel and temporal object recognition and show corresponding traits in brain MRI

Abstract

Recent clinical trials targeting tau protein aggregation have heightened interest in tau-based therapies for dementia. Success of such treatments depends crucially on translation from non-clinical animal models. Here, we present the age profile of the PLB2_Tau knock-in model of fronto-temporal dementia in terms of cognition, and by utilising a directly translatable magnetic resonance imaging approach. Separate cohorts of mice aged 3, 6 and 12 months were tested in an object recognition protocol interrogating visual, spatial, and temporal discrimination in consecutive tests. Upon completion of their behavioural testing, animals were recorded in a 7 T MRI for brain structural integrity and diffusion tensor imaging (DTI) analysis. We report that PLB2_Tau mice presented with an age-dependent deficit in novel object discrimination relative to wild-type controls at 6 and 12 months. Spatial and temporal discrimination, though not significantly different from controls, appeared extremely challenging for PLB2_Tau subjects, especially at 12 months, since they explored objects less than controls and were devoid of memory. Controls readily recalled all relevant object-related information. At the same time, the T2 weighted voxel-based image analysis revealed a progressive shrinkage of total brain volumes in 6- and 12-month-old PLB2_Tau mice as well as relative striatal, but not hippocampal volumes. A regional DTI analysis yielded only reduced mean diffusivity of the fimbria, but not CA1 or dentate gyrus, amygdala, cingulate cortex, or corpus callosum. These data confirm the PLB2_Tau mouse as a translationally useful model for dementia research and suggest the importance of the hippocampal input as a determinant for novel object discrimination.