What is the pathological significance of tau oligomers?

Insoluble aggregates of the microtubule-associated protein tau characterize a number of neurodegenerative diseases collectively termed tauopathies. These aggregates comprise abnormally hyperphosphorylated and misfolded tau proteins. Research in this field has traditionally focused on understanding how hyperphosphorylated and aggregated tau mediates dysfunction and toxicity in tauopathies. Recent findings from both Drosophila and rodent models of tauopathy suggest that large insoluble aggregates such as tau filaments and tangles may not be the key toxic species in these diseases. Thus some investigators have shifted their focus to study pre-filament tau species such as tau oligomers and hyperphosphorylated tau monomers. Interestingly, tau oligomers can exist in a variety of states including hyperphosphorylated and unphosphorylated forms, which can be both soluble and insoluble. It remains to be determined which of these oligomeric states of tau are causally involved in neurodegeneration and which signal the beginning of the formation of inert/protective filaments. It will be important to better understand this so that tau-based therapeutic interventions can target the most toxic tau species.