Legumain/asparaginyl endopeptidase-resistant tau fibril fold produces corticobasal degeneration-specific C-terminal tau fragment.

Abstract

Corticobasal degeneration (CBD) is a major four-repeat tauopathy along with progressive supranuclear palsy (PSP). Although detergent-insoluble 37-40-kDa carboxyl-terminal tau fragments (CTFs) are hallmarks of CBD pathology, the process of their formation is unknown. This study monitored the formation of CBD-type fibrils that exhibit astrocytic plaques, a characteristic CBD pathology, using its biochemical properties different from those of Alzheimer's disease/PSP-type fibrils. Tau fibrils from patients with CBD were amplified in non-astrocytic cultured cells, which maintained CBD-specific biochemical properties. We found that the lysosomal protease Legumain (LGMN) was involved in the generation of CBD-specific 37-40-kDa CTFs. While LGMN cleaved tau fibrils at Asn167 and Asn368 in the brain tissues of patients with Alzheimer's disease and PSP, tau fibrils from patients with CBD were predominantly resistant to cleavage at Asn368 by LGMN, resulting in the generation of CBD-specific CTFs. LGMN preference in tau fibrils was lost upon unraveling the tau fibril fold, suggesting that the CBD-specific tau fibril fold contributes to CBD-specific CTF production. From these findings, we found a way to differentiate astrocytic plaque from tufted astrocyte using the anti-Asn368 LGMN cleavage site-specific antibody. Inoculation of tau fibrils amplified in non-astrocytic cells into the mouse brain reproduced LGMN-resistant tau fibrils and recapitulated anti-Asn368-negative astrocytic plaques, which are characteristic of CBD pathology. This study supports the existence of disease-specific tau fibrils and contribute to further understanding of the tauopathy diagnosis. Our tau propagation mouse model using cellular tau seeds may contribute to uncovering disease mechanisms and screening for potential therapeutic compounds.