The formation of small aggregates contributes to the neurotoxic effects of tau.

Intracellular deposits of hyperphosphorylated tau are commonly detected in tauopathies. Furthermore, these aggregates seem to play an important role in the pathobiology of these diseases. In the present study, we determined whether the recently identified neurotoxic tau fragment also formed aggregates in neurodegenerative disorders. The presence of such aggregates was examined in brain samples obtained from Alzheimer's disease (AD) subjects by means of Western blot analysis performed under non-denaturing conditions. Our results showed that a mixture of tau oligomers of different sizes was easily detectable in brain samples obtained from AD subjects. Our data also suggested that tau oligomers could be internalized by cultured hippocampal neurons, mainly through a clathrin-mediated mechanism, triggering their degeneration. In addition, in vitro aggregation studies showed that tau modulated full-length tau aggregation thereby inducing the formation of smaller, and potentially more toxic, aggregates of this microtubule-associated protein. Together, these data identified alternative mechanisms underlying the toxic effects of tau.