Caspase-6-cleaved tau is relevant in Alzheimer’s disease but not in other tauopathies: diagnostic and therapeutic implications

Abstract

AimTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates toxic tau fragments prone to self-aggregation. Yet, the relationship between aCasp-6, different forms of tr-tau, and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer’s disease (AD) and other tauopathies remains unclear.MethodsWe generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used 5-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau, and their co-occurrence in healthy controls, AD, and primary tauopathies.ResultsCasp-6 activation was strong in AD, followed by Pick’s disease (PiD), but almost absent in 4-repeat (4R) tauopathies. Tr-tau neuronal burden was much higher in AD than in 4R tauopathies, and disproportionally higher when normalizing by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, half of the tr-tau positive neurons in AD lacked p-tau aggregates.ConclusionsEarly modulation of aCasp-6 with consequent amortization of tr-tau pathology is a promising therapeutic strategy in AD and possibly PiD, but it is unlikely to benefit 4R tauopathies. The large percentage of tr-tau neurons lacking p-tau suggests that not all tau pathology and vulnerable neurons are detected by conventional p-tau Ser 202 antibody and, that AD, has distinct mechanisms of tangle formation. Therapeutic strategies against tr-tau pathology could modulate tau abnormalities in AD. The disproportional higher burden of tr-tau in AD supports the evaluation of biofluid biomarkers against N-terminus tr-tau to detect AD and differentiate it from 4R tauopathies at a single patient level.