Lifetime brain structural trajectories in TAUPS2APP mouse model of Alzheimer's disease

Abstract Background The TAUPS2APP Alzheimer’s disease (AD) mouse model expresses mutant APPSWE, PSEN2N141I and TAUP301L mutations and displays age‐dependent accumulation of Aβ plaques and neurofibrillary tangles. In humans, abnormal protein accumulation and spreading are related to neurodegenerative processes, most stereotypically in the hippocampus and medial temporal lobe. Prior reports in different AD models have demonstrated various brain structural phenotypes (Grandjean et al.,2016). Here we assess neuroanatomical trajectories in the TAUPS2APP model of AD using longitudinal MRIs. Method Thirteen C67BL/6 (11f/2m) and seventeen TAUPS2APP (10f/7m) mice underwent T2‐weighted MRI (voxel size 117x147x147 μm, matrix 256x102x120, FoV 3x1.5x1.5 cm, TR=2500 ms TE=50 ms) at 4,9,13,18, and 24 months of age. Data were analyzed following two‐level deformation‐based morphometry pipeline that uses ANTs SyN nonlinear registration. At the first level within subjects’ minimum deformation averages are created and estimates of volume change are computed (log Jacobian determinants). Next, a second level average is created out of unbiased within‐subject averages and the Jacobians are resampled into the common space Result A linear mixed‐effect model with subject as random effect (second order spline fit, sex as a covariate) revealed significant differences in interaction between age and genotype in neuroanatomical trajectory (absolute Jacobian) of bilateral hippocampus, lateral septal area (LSA) and isocortical areas (at False Discovery Rate of 5%, fig.1). TAUPS2APP showed an accelerated overgrowth of hippocampus at young age but larger volumetric decline with age in comparison to non‐TG animals (fig.2a). A similar pattern was observed in LSA (fig.2b). On the contrary in the isocortex, where non‐TG declined with age, TAUPS2APP mice showed volume enlargement (fig. 3c). Conclusion These data suggest that TAUPS2APP model is characterized by abnormal neuroanatomical trajectory throughout its lifespan relative to controls. While hippocampal atrophy recapitulates clinical markers of late‐onset AD, enlarged cortex that had been reported earlier in some AD mouse models (TgCRND8, APP/J20 and PSAPP) does not. It was suggested that elevated APP levels may affect the rate of local region growth in adult mice ‐ due to space occupancy by amyloidosis and astrogliosis. In line with this Maheswaran et al. had reported a link between transgene expression, age, and volume increase over time (Maheswaran et al., 2009).

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