C-terminal truncation modulates both nucleation and extension phases of τ fibrillization

Proteolytic post-translational modification has been proposed as an early stage event in the aggregation of T protein and formation of neurofibrillary lesions in Alzheimer's disease. Caspases and other proteases cleave tau in vivo at discrete locations including Asp(421) and Glu(391). Both cleavage products are prone to aggregation relative to wild-type, full-length T protein. To determine the mechanism underlying this effect, the fibrillization Of tau truncated after Asp(421) and Glu(391) residues was characterized in a full-length four-repeat tau background using quantitative electron microscopy methods under homogeneous nucleation conditions. Both C-terminal truncations decreased critical concentration relative to full-length tau, resulting in more filament mass at reaction plateau. Moreover, truncation directly augmented the efficiency of the nucleation reaction. The results suggest the mechanism through which C-terminal proteolysis can modulate tau filament accumulation depending on whether it precedes or follows nucleation. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.