Seeding and spreading of Tau pathology in TauP301S mice

Tau pathology was seeded by injecting hyperphoshorylated aggregated Tau in the hippocampus of young hTau[P301S] mice, which haven’t developed any Tau pathology yet. A brainstem homogenate of old hTau[P301S] mice with high levels of Tau pathology were used as a source of hyperphosphorylated aggregated Tau and a brainstem homogenate of age matched non-transgenic mice was used as a negative  control. 9 weeks after injection, the level of AT8-positive neurofibrillary tangle-like inclusions was strongly increased in the ipsilateral hippocampus (site of injection) when compared to the negative control (Figure 1, left). Moreover, the Tau pathology has spread to the contralateral hippocampus (opposite of the injection site) and is significantly higher than the negative control (Figure 1, right).

These data show the brainstem homogenate of hTau[P301S] can be used as a very potent seed of Tau pathology in hTau[P301S] mice and spreads to the contralateral hippocampus. Representative images of the hippocampus are shown in Figure 2.

Figure 1

Figure 1: Quantification of AT8 (pTAU S202/T205) IHC staining 9 weeks after injection with brain stem homogenate of end-stage Tau[P301S] mice (dark green) or non transgenic mice as a negative control (light green). Left: Seeding potential in the ipsilateral hippocampus. Right: Spreading potential in the contralateral hippocampus.

Figure 2

Figure 2: Representative images of the AT8 (pTAU S202/T205) IHC staining 9 weeks after injection with brain stem homogenate (BSH) of non transgenic mice as a negative control (top) or end-stage Tau[P301S] mice (bottom). Left: Seeding potential in the ipsilateral hippocampus. Right: Spreading potential in the contralateral hippocampus.

Seeding and spreading of Tau pathology in TauP301L mice

Seeding and spreading of K18 preformed Tau fibrils (PFF kindly provided by StressMarq Biosciences) was also investigated in hTau[P301L] mice. To this end K18 PFFs or PBS as a negative control were injected in the hippocampus of hTau[P301L]. 9 weeks after injection, the level of AT8-positive neurofibrillary tangle-like inclusions were significantly increased both in the ipsilateral hippocampus (i.e. seeding) and the contralateral hippocampus (i.e. spreading) when compared to the negative control (Figure 3), albeit more limited in the contralateral hippocampus. Representative figures of the hippocampus are shown in Figure 4.

Figure 3

Figure 3: Quantification of AT8 (pTAU S202/T205) IHC staining 9 weeks after injection with K18 mutant preformed fibrils (PFF) (dark colours) or non transgenic mice as a negtaive control (light colours). Left: Seeding potential in the ipsilateral hippocampus. Right: Spreading potential in the contralateral hippocampus.

Figure 4

Figure 4: Representative images of the AT8 (pTAU S202/T205) IHC staining 9 weeks after injection with brain stem homogenate of non transgenic mice as a negative control (top) or K18 mutant preformed fibrils (PFF) (bottom). Left: Seeding potential in the ipsilateral hippocampus. Right: Spreading potential in the contralateral hippocampus.