Insights into the mechanism of Tau amyloid assembly using anionic inducer

Abstract

Tau is a natively unfolded or an intrinsically disordered (IDP) protein which is also known to form ordered -sheet-rich amyloid fibrils that are implicated in various neurodegenerative disorders such as frontotemporal dementia, Down’s syndrome, Alzheimer’s disease etc. Studies have indicated that Tau forms paired helical filaments which subsequently transform into neurofibrillary tangles that result in various tauopathies associated with declining cognition abilities. It has been demonstrated that the Tau repeat domain is the primary component of the amyloid core present in the paired helical filaments and consequently, studying the amyloid formation mechanism of tau repeat domain has generated a lot of interest over the past few years. In this research work we have mainly focused on the repeat domain of Tau i.e. Tau K18 for aggregation because it is known in literature that the repeat region of tau is more prone to aggregation. Earlier reports have revealed that tau aggregation in vitro is triggered by anionic inducers, however, the molecular mechanism of Tau amyloid aggregation still remains elusive. Here, we have investigated the amyloid aggregation mechanism of Tau K18 using a well-known lipid mimetic and an anionic inducer namely, sodium dodecyl sulphate (SDS) at sub-micellar concentration by spectroscopic techniques such as fluorescence and circular dichroism (CD) in addition to biochemical techniques and atomic force microscopy. Our findings indicate that TauK18 amyloid aggregation proceeds via a nucleation-dependent polymerization mechanism mediated via electrostatic interactions. Additionally, formation of a partially α-helical intermediate occurs at the initial time-points which is an aggregation-competent conformer that eventually transforms into cross -sheetrich amyloid fibrils.