Are Tau Aggregates Toxic or Protective in Tauopathies?

Aggregation of highly phosphorylated tau into aggregated forms such as filaments and neurofibrillary tangles is one of the defining pathological hallmarks of Alzheimer's disease and other tauopathies. Hence therapeutic strategies have focused on inhibition of tau phosphorylation or disruption of aggregation. However, animal models imply that tau-mediated dysfunction and toxicity do not require aggregation but instead are caused by soluble hyper-phosphorylated tau. Over the years, our findings from a Drosophila model of tauopathy have reinforced this. We have shown that highly phosphorylated wild-type human tau causes behavioral deficits resulting from synaptic dysfunction, axonal transport disruption, and cytoskeletal destabilization in vivo. These deficits are evident in the absence of neuronal death or filament/tangle formation. Unsurprisingly, both pharmacological and genetic inhibition of GSK-3β rescue these tau phenotypes. However, GSK-3β inhibition also unexpectedly increases tau protein levels, and produces insoluble granular tau oligomers. As well as underlining the growing consensus that tau toxicity is mediated by a highly phosphorylated soluble tau species, our findings further show that not all insoluble tau aggregates are toxic. Some tau aggregates, in particular tau oligomers, are non-toxic, and may even be protective against tau toxicity in vivo. This has serious implications for emerging therapeutic strategies to dissolve tau aggregates, which might be ineffective or even counter-productive. In light of this, it is imperative to identify the key toxic tau species and to understand how it mediates dysfunction and degeneration so that the effective disease-modifying therapies can be developed.