O4‐05‐05: prevention of tau seeding and spreading in transgenic mouse models based on intracranial‐injection of p301l‐k18 fibrils or alzheimer's disease lysate by passive immunotherapy

In tauopathies such as Alzheimer's disease (AD), Tau protein becomes pathologically hyperphosphorylated leading to its intracellular accumulation and aggregation which will progressively cause neuronal loss and cognitive decline. Anti-Tau immunotherapy is increasingly considered as a potential treatment to block progression of tauopathies. We report that anti-Tau antibody treatment reduces Tau seeding & spreading in two mouse models of tauopathy. Previously, we showed that an anti-Tau antibody (Ab) produced by UCB Pharma, is able to block Tau aggregation induced by AD patient-derived materials in vitro. Here, we used two in vivo transgenic mouse (tg) models of tauopathies: First, a seed model, based on the unilateral injection of AD brain lysate into the hippocampus of THYTau30 transgenic mice before the appearance of basal pathology due to transgene expression. Second, a model of Tau spreading, by injecting P301L-K18 tau preformed fibrils in P301L tg mice. Tau pathology induced by seed injection was quantified in the ipsi and contralateral hippocampus after weekly intraperitoneal injections of the anti-Tau Ab or negative control. Hyperphosphorylated abnormal Tau species were detected in brain sections using AT8 (pSer202, pThr205 Tau) or AT100 (pThr212, pSer214) Abs. Tau pathology was then quantitatively analyzed using Mercator (Explora Nova, La Rochelle, France). In the seed model, the anti-Tau Ab reduced the AT8 (p<0.001) and AT100 (p<0.01) immunoreactivity by 80% compared to negative control antibody. Significant reduction of Tau pathology was observed in both the ispi and contralateral hippocampus. In the P301L-K18 injection-based model, the anti-Tau Ab significantly reduced secreted Tau spreading in the contralateral hippocampus compared with the negative control (p<0.05). Our data show that the anti-Tau Ab reduces not only Tau pathology induced by intracranial injection of human seeds but also the transynaptic spreading of Tau pathology. Investigations are now under way to determine the mechanisms by which the anti-Tau Ab reduces Tau pathology mediated by extracellular pathological Tau species.