학술논문
Caspase‐6‐cleaved tau is relevant in Alzheimer's disease and marginal in four‐repeat tauopathies: Diagnostic and therapeutic implications
Document Type
article
Author
Theofilas, Panos; Piergies, Antonia MH; Oh, Ian; Bin Lee, Yoo; Li, Song Hua; Pereira, Felipe L; Petersen, Cathrine; Ehrenberg, Alexander J; Eser, Rana A; Ambrose, Andrew J; Chin, Brian; Yang, Teddy; Khan, Shireen; Ng, Raymond; Spina, Salvatore; Seeley, Willian W; Miller, Bruce L; Arkin, Michelle R; Grinberg, Lea T
Source
Neuropathology and Applied Neurobiology. 48(5)
Subject
Language
Abstract
AimTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates tau fragments that may be toxic. 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 five-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 strongest in AD and Pick's disease (PiD) but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD and PiD than in 4R tauopathies and disproportionally higher when normalising by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr-tau positive neurons in AD and PiD lacked p-tau aggregates, a finding we confirmed using several p-tau antibodies.ConclusionsEarly modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD and PiD but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that many vulnerable neurons to tau pathology go undetected when using conventional p-tau antibodies. Therapeutic strategies against tr-tau pathology could be necessary to modulate the extent of tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD and PiD supports the development of biofluid biomarkers against tr-tau to detect AD and PiD and differentiate them from 4R tauopathies at a patient level.