Investigating the Effects of N-Terminal Tau Truncation in the Pathogenesis of Alzheimer's Disease

The tau protein is involved in microtubule dynamics and is found in the cytoskeleton of neuronal cells. Phosphorylation of the tau protein results in detachment from the microtubule, leading to the formation of tau aggregates. These aggregates are observed in the brains of patients with Alzheimer’s disease. Furthermore, aggregate presence and number in the brain correlates strongly with cognitive decline; thus, the process through which tau can become misfolded and aggregated is a key area of study. Tau cleavage, or the removal of a portion of the protein from one or both of its termini, is a type of modification that is thought to influence the formation of tau aggregates.  The impacts of cleaving tau from the N-terminus, or amino-terminus, are poorly understood. Cleaved tau fragments lacking the extreme N-terminus have been identified in the cerebrospinal fluid of individuals with AD, implicating N-terminal cleavage as a potential mechanism involved in disease progression. Here, we demonstrate that cells expressing tau cleaved from the N-terminus produce tau aggregates that have a distinct phosphorylation signature and a unique morphology that is different from full length tau aggregates. We also show that cells expressing N-terminally cleaved tau contain early pathological tau species thought to spread to nearby neurons. The results of this work demonstrate a potential role for the N-terminus in mediating early pathological tau formation and could identify this domain as a key area to target for future therapeutic intervention.