Injection of purified tau aggregates from tauopathy patients into the mouse brain can recapitulate main pathological features of the patients tauopathy. This approach thus allows to analyze tauopathy-specific pathologies with a high translational value.
For the injection, 9-10 weeks old hTau mice expressing human tau but lacking endogenous tau were used. Mice were unilaterally injected into the hippocampus and overlying parietal cortex with sarkosyl-insoluble tau seeds of patients with AD Braak stage VI. 12 weeks after the injection, animals were sacrificed, and brains were analyzed for pathological changes of phosphorylated tau at serine 202 / threonine 205 (pSer202/pThr205). Phosphorylated tau was measurable not only in the cortex and hippocampus of the ipsi- but also of the contralateral hemisphere, indicating tau seeding as well as tau spreading to the contralateral side (Figure 1).
Figure 1: pSer202/pThr205 Tau immunoreactivity in the parietal cortex (A) and hippocampus (B, C) of the contra- and ipsilateral hemisphere after unilateral AD brain seed injection into the hippocampus and overlying cortex of the ipsilateral hemisphere. Animals were euthanized 12 weeks after injection and brains were evaluated using AT8 antibody. IR = immunoreactive area. n = 8 / group; 2-way ANOVA followed by Šídák´s post hoc test for multiple comparisons; Mean + SEM. *p<0.05; ***p<0.001.
Immunohistological analysis of brain tissue sections using markers for labeling neurons, astrocytosis and cell nuclei revealed structural changes of the dentate gyrus granule cell layer of the injected, ipsilateral, hemisphere (Figure 2).
Figure 2: Immunofluorescent labeling of NeuN, as marker of neuronal somata, as well as glial fibrillary acidic protein (GFAP) as marker of astrocytosis, and DAPI staining to visualize cell nuclei. Note structural changes of the dentate gyrus granule cell layer between the tau seed-injected ipsilateral and the contralateral control side (white arrow heads).
Our results suggest that seeding of AD patient-derived tau aggregates closely mimics tauopathies on a structural and physiological level and therefore making this model a valuable tool to study tauopathy.