Severe oligomeric tau toxicity can be reversed without long-term sequelae

Abstract Tau is a microtubule stabilizing protein that forms abnormal aggregates in many neurodegenerative disorders, including Alzheimer’s disease. We have previously shown that co-expression of fragmented and full-length tau in P301SxTAU62on tau transgenic mice results in the formation of oligomeric tau species and causes severe paralysis. This paralysis is fully reversible once expression of the tau fragment is halted, even though P301S tau expression is maintained. Whereas various strategies to target tau aggregation have been developed, little is known about the long-term consequences of reverted tau toxicity. Therefore, we studied the long-term motor fitness of recovered, formerly paralysed P301SxTAU62on-off mice. To assess the seeding competence of oligomeric toxic tau species, we also inoculated ALZ17 mice with brainstem homogenates from paralysed P301SxTAU62on mice. Counter-intuitively, after recovery from paralysis due to oligomeric tau species expression, ageing P301SxTAU62on-off mice did not develop more motor impairment or tau pathology when compared to heterozygous P301S tau transgenic littermates. Thus, toxic tau species causing extensive neuronal dysfunction can be cleared without inducing seeding effects. Moreover, these toxic tau species also lack long-term tau seeding effects upon intrahippocampal inoculation into ALZ17 mice. In conclusion, tau species can be neurotoxic in the absence of seeding-competent tau aggregates, and mice can clear these tau forms permanently without tau seeding or spreading effects. These observations suggest that early targeting of non-fibrillar tau species may represent a therapeutically effective intervention in tauopathies. On the other hand, the absent seeding competence of early toxic tau species also warrants caution when using seeding-based tests for preclinical tauopathy diagnostics.