Caspase-6-cleaved tau is relevant in Alzheimer's disease and marginal in four-repeat tauopathies: Diagnostic and therapeutic implications.

Autor: Theofilas P; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA., Piergies AMH; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA., Oh I; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA., Lee YB; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA., Li SH; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA., Pereira FL; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA., Petersen C; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA., Ehrenberg AJ; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA., Eser RA; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA., Ambrose AJ; Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, USA., Chin B; Shanghai ChemPartner, Shanghai, China., Yang T; Shanghai ChemPartner, Shanghai, China., Khan S; ChemPartner San Francisco, South San Francisco, California, USA., Ng R; ChemPartner San Francisco, South San Francisco, California, USA., Spina S; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA., Seeley WW; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA.; Department of Pathology, University of California San Francisco, San Francisco, California, USA., Miller BL; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA.; Global Brain Health Institute, University of California San Francisco, San Francisco, California, USA., Arkin MR; Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, USA., Grinberg LT; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA.; Department of Pathology, University of California San Francisco, San Francisco, California, USA.; Global Brain Health Institute, University of California San Francisco, San Francisco, California, USA.; Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil.
Jazyk: angličtina
Zdroj: Neuropathology and applied neurobiology [Neuropathol Appl Neurobiol] 2022 Aug; Vol. 48 (5), pp. e12819. Date of Electronic Publication: 2022 Jun 02.
DOI: 10.1111/nan.12819
Abstrakt: Aim: Tau 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.
Methods: We 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.
Results: Casp-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.
Conclusions: Early 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.
(© 2022 British Neuropathological Society.)
Databáze: MEDLINE
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