A Caspase Cleaved Form of Tau Is Preferentially Degraded through the Autophagy Pathway

The microtubule-associated protein tau plays a central role in the pathogenesis of Alzheimer disease (AD) and abnormally accumulates as neurofibrillary tangles; therefore, the pathways by which tau is degraded have been examined extensively. In AD brain tau is abnormally truncated at Asp(421) (tau Delta C), which increases its fibrillogenic properties and results in compromised neuronal function. Given the fact that the accumulation of tau Delta C is a pathogenic process in AD, in this study we examined whether full-length tau and tau Delta Care degraded through similar or different mechanisms. To this end a tetracycline-inducible model was used to show that tau Delta C was degraded significantly faster than full-length tau (FL-tau). Pharmacological inhibition of the proteasome or autophagy pathways demonstrated that although FL-tau is degraded by the proteasome, tau Delta C is cleared predominantly by macroautophagy. We also found that tau Delta C binds C terminus of Hsp70-interacting protein more efficiently than tau. This interaction leads to an increased ubiquitylation of tau Delta C in a reconstituted in vitro assay, but surprisingly, tau (full-length or truncated) was not ubiquitylated in situ. The finding that tau Delta C and FL-tau are differentially processed by these degradation systems provides important insights for the development of therapeutic strategies, which are focused on modulating degradation systems to preferentially clear pathological forms of the proteins.