The Role of the N-terminus of Tau in Alzheimer's DiseasePublic Deposited
The polymerization of the microtubule-associated protein, tau, into insoluble filaments is common to Alzheimer's disease (AD) and in a variety of dementias. The conformational change required for tau to transition from soluble monomers to filamentous AD pathology involves the extreme N-terminus of tau coming into contact with other regions of the molecule; however, these exact interactions are complex and incompletely understood. Furthermore, this process may be regulated by phosphorylation, enzymatic cleavage, and other post-translational modifications at the N-terminus and elsewhere. Such modifications have been well documented at the C-terminus of the molecule during the evolution of the neurofibrillary tangles of AD. However, N-terminal processing of tau remains largely uncharacterized. The aim of this project was to investigate the role of the N-terminus in tau polymerization and trace the changes that occur at the N-terminus during the evolution of AD pathology. The role of the N-terminus in polymerization was investigated by generating recombinant N-terminal fragments of tau. A construct representing the amino half of tau, which itself does not polymerize, inhibits polymerization of full-length tau (hTau40) in vitro. The inhibitory effect requires specific residues of the N-terminal fragment and hTau40. Furthermore, the fragments appear to exert their effects by interacting with soluble tau species. These results suggest a novel regulatory role for the N-terminus of tau in polymerization. Immunohistochemical examination of the N-terminus of tau in AD pathology using a panel of N-terminal anti-tau antibodies showed significant differences in the number and morphology of tangles stained, suggesting an early event which unmasks an N-terminal epitope. Later in tangle evolution, the loss of extreme N-terminal epitopes correlated with the appearance of a C-terminal caspase-cleaved epitope, suggesting a role for caspases in N-terminal processing of tau. In support of this hypothesis, caspase-6 cleaved the N-terminus of tau in vitro at D13, a novel caspase cleavage site in tau, preventing immunoreactivity with N-terminal antibodies. Another protease, puromycin-sensitive aminopeptidase, also digests tau from the N-terminus in vitro. Collectively, these results may account for an N-terminal truncation of tau and disappearance of N-terminal tau epitopes during neurofibrillary tangle evolution and the progression of Alzheimer's disease.