Targeting aggregated tau turnover as a therapeutic strategy

Abstract

The accumulation of microtubule-associated protein tau in intracellular inclusions is a common feature of Alzheimer's disease and other tauopathies. We have recently identified using optical pulse labelling methodology (OPL) that neurofibrillary tau inclusions comprised of aggregated tau are dynamic structures that show turnover of aggregated tau. This occurs in both intrinsically formed and exogenously seeded tau inclusions. Understanding the mechanisms by which this turnover occurs could inform how to most appropriately treat tauopathies.Using recombinant adeno-associated viruses (rAAVs) we are able to deliver Dendra2-tagged pro-aggregant and non-aggregating tau to murine brain slice cultures with and without the application of exogenous tau seeds. These methods facilitate the long-term tracking of tau inclusion dynamics using OPL methodology. In combination with these methods, we can begin to assess whether compounds, monoclonal antibodies or other potential therapeutic modulators change tau aggregate turnover or affect tau by differential mechanisms.Using OPL, we can track the formation of neurofibrillary tau inclusions and the kinetics of tau turnover. We find that newly formed tau inclusions show turnover, but with ageing in culture the rate of turnover slows. Using this experimental paradigm, we now aim to begin to understand the mechanisms that facilitate this turnover and determine whether therapies that affect this turnover may be beneficial. We also find that a compound known to reduce tau pathology reduces tau phosphorylation and tau insolubility but does not affect the rate of tau production or clearance.Our OPL studies have documented that neurofibrillary tau inclusions comprised of aggregated tau show daily turnover of tau, at least when initially formed. We now aim to use this system to begin to understand the cellular processes that facilitate this tau inclusion turnover. Furthermore, understanding these mechanisms may lead to new therapeutic strategies for Alzheimer's disease and other neurodegenerative conditions where tau plays a role.