Tau Oligomers in Alzheimer's Disease: Modulation Effect of Osmolytes on Amplified Brain-Derived Tau Oligomers.

Tau is bound to microtubules and plays a key role in their assembly and spatial organization. Under pathological conditions, tau detaches from the microtubules and develops a propensity to self-aggregate into soluble tau oligomers (TauO), paired helical filaments, and neurofibrillary tangles. Recent studies have revealed that TauO is the toxic species responsible for seeding, propagation, and development of tauopathies. Strategies that can modulate the process of TauO formation can help reduce the toxicity of TauO and stop the progression of the disease. Osmolytes are naturally occurring small-molecular-weight organic compounds, which crucially assist in the proper protein folding and thus impact the stability and solubility of proteins. Therefore, osmolytes can serve as good candidates for modulating TauO. Osmolytes cross the blood-brain barrier and act as chaperons to prevent the proteins from misfolding and aggregation. Here, we investigated the effect of different brain osmolytes against the amplified brain-derived tau oligomer (aBDTO). Our investigations have revealed that the brain osmolytes modulate the aBDTO differentially. The osmolytes sorbitol and glycerophosphocholine (GPC) displayed the potential to reduce the formation and accumulation of large aggregates by disaggregating the precursor tau oligomers into smaller assemblies with varying conformations. This may result from these osmolytes modulating the conformation of aggregated tau, which could lead to reduction in its seeding potential. However, trimethyl amine oxide (TMAO) has been found to prevent and clear out the formation of aBDTO significantly. Citrulline is less effective than TMAO and possibly affects more dimeric species. These osmolytes can become an indispensable tool for the management of Alzheimer's disease and part of hybrid therapeutic mechanisms, in addition to providing better understanding of tau oligomerization and seeding ability.