Biochemical and structural characterization of tau oligomers and cerebrospinal-fluid-derived tau in murine models of tauopathy

Tau is a microtubule stabilizing protein that forms aggregates in Alzheimer’s disease (AD). Tau protein abnormal aggregation is one of the main pathological features in AD patients’ brain, particularly in the forms of insoluble tau fibrils. However, in recent years, a more prominent role in pathogenesis and diagnosis of AD has been increasingly given also to soluble tau oligomers and tau fragmentation pathways as well.
It was previously shown that fragmentation is linked to oligomeric stress in murine models of tauopathy, as co-expression of fragmented and full-length tau in tau transgenic mice results in the formation of oligomeric, non-fibrillary tau species and causes severe paralysis. This paralysis is fully reversible once expression of the tau fragment is halted, even though mutant 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.
Tau fragments constitute also the majority of the protein reaching the cerebrospinal fluid (CSF) compartment. CSF-derived tau is a key diagnostic biomarker for AD; however, its features are largely unknown. Particularly, it is an unresolved question whether CSF-derived tau possesses a seeding competence. Previous in vivo studies on CSF-derived Aβ proved that this other biomarker does not have a seeding potential; however, in vitro studies on CSF-derived tau pointed towards another direction. Therefore, it was investigated whether CSF collected from patients diagnosed with probable AD or mild cognitive impairment (MCI) likely due to AD harbors a prion-like tau seeding potential.
The present thesis shows that 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.
The results of the thesis provide also first evidence for in vivo prion-like properties of AD patients’ CSF, accelerating tau pathology in susceptible tau transgenic mice. This demonstrates that biologically active tau seeds reach the CSF compartment in AD. Further studies may help to evaluate strain specific properties of CSF-derived tau bioseeds, and to assess their diagnostic potential.
In conclusion, the results presented in the thesis follow therefore nascent lines of research where oligomers are questioning the importance of established hallmarks in neurodegenerative diseases, and oligomerization might be indeed linked to fragmentation of protein at the center of neurological proteinopathies and be a suitable target for therapeutic strategies; furthermore, these results also call for the importance and specificity of tau biomarkers for AD diagnosis, and this newfound seeding competence of CSF-tau could therefore improve the diagnostic tools at our disposal