Extracellular oligomeric Tau impairs synaptic plasticity and memory independently of Aβ

Amyloid-β (Aβ) and Tau play a key role in Alzheimer’s disease (AD) pathogenesis. In particular, soluble oligomeric forms of these peptides (oAβ and oTau) are thought to mediate the early synaptic damage occurring several years before clinical manifestations. According to the prevailing hypothesis, Aβ triggers Tau pathology, which in turn spreads throughout the cortex leading to memory loss. Therefore, anti-Aβ therapies might be not effective if Tau pathology has been already triggered. On the other hand, Tau exerts a toxic effect per se in tauopathies, where Aβ is not involved. Based on this evidence, here, we aimed to better understand the relationship between oAβ and oTau in inducing synaptic plasticity and memory impairment. Our results showed that a brief exposure to oTau produced an immediate impairment of long-term potentiation (LTP) and memory, per se, i.e. independently of Aβ. This toxic effect was validated by using recombinant human oTau, oTau extracted from AD human specimens or human oTau produced in transgenic mice. However, oTau can act concurrently with oAβ, since a co-administration of sub-toxic doses of these peptide lead to an impairment of LTP and memory. Interestingly, both oTau and oAβ are able to enter neurons. In conclusion, we have shown that oTau and oAβ, alone or in combination, impaired LTP and memory, challenging the classical view that oAβ acts as a primum movens to induce amnestic changes via Tau. Outcomes from this study might be useful to develop new drugs acting on a common oAβ and oTau target.