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 nonclinical animal models. Here, we present the age profile of the PLB2Tau 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 7T MRI for brain structural integrity and diffusion tensor imaging (DTI) analysis.
We report that PLB2Tau 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 PLB2Tau 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 PLB2Tau 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 PLB2Tau mouse as a translationally useful model for dementia research and suggest the importance of the hippocampal input as a determinant for novel object discrimination.