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.

Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

“…These findings are consistent with a gradual increase in the intracellular steady-state expression level of the neurotoxic NH 2 htau we detected over time by Western blotting analysis on hippocampi from mice injected with STZ (3 mg/Kg) for 7, 14, 21 days (Figure S1). Besides, our biochemical results point out that the detrimental effects of toxic non-fibrillary tau species are reversible in vivo within a certain frame of time [90], when a biologically efficacy, therapeutic concentration of neutralizing antibody is reached.…”

NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease

“…Tau is a soluble protein acting as a microtubule stabilizer in neuronal cells [ 19 ]. It participates in the stabilization of microtubules, by binding to their surface, and fosters microtubules’ self-assembly [ 18 ].…”

“…Self-aggregation of tau and further recruitment of more tau monomers and dimers creates a nucleation center that harbors the process of oligomerization [ 23 ]. Tau oligomers then acquire a β-sheet structure, with subsequent aggregation into fibrils, culminating in the formation of NFTs [ 19, 20 ]. As observed for Aβ, intermediate species generated during the formation of tangles, are the most toxic ones affecting neuronal and synaptic function [ 20 ].…”

Lysine 63-linked ubiquitination of tau oligomers contributes to the pathogenesis of Alzheimer’s disease

“…We have identified an association of K63-linked ubiquitin with pathological tau in postmortem AD brain tissues, particularly in the soluble fraction containing the most toxic oligomeric tau form (Fig. 7) [46][47][48], which has not been studied before. To identify the signature peptides of ubiquitination on tau oligomer, a combination of immunoprecipitation with a highly sensitive and specific mass spectrometry method using selected reaction monitoring (SRM) demonstrated that tau was ubiquitinated at microtubule-binding regions (MTBR) and the C-terminal domains including K254, K311, K353, K385, and K395 residues.…”