OLIGOMERIC TAU IMPAIRS SYNAPTIC PLASTICITY AND MEMORY

Background - Amyloid-β (Aβ) peptide and Tau are considered key pathogenetic factors in Alzheimer’s disease (AD), leading to the formation of senile plaques and neurofibrillary tangles, respectively. Further researches have evidenced an interaction between Aβ and Tau. In particular, oligomeric Aβ is thought to trigger Tau pathology, which in turn spreads throughout the medial temporal cortex and neocortices independently of Aβ, inducing the consequential synaptic loss. As AD progresses, extracellular soluble forms of Tau might transmit pathology from neuron to neighboring neurons. Here we report our recent data demonstrating that different oligomeric forms of tau (oTau) affect memory and its molecular correlate, long-term potentiation (LTP). Methods - We used 3-4 months old C57Bl/6J wild type mice. Electrophysiological studies were performed by extracellular field recordings on hippocampal slices in vitro. We explored hippocampal synaptic plasticity by studying LTP in CA1 area, and whether it was affected by the administration of oTau 4R/2N or an enriched preparation in soluble human Tau extracted from AD patients (AD-Tau). We also evaluated the effects of Tau 4R/2N or AD-Tau on fear memory by using Fear Conditioning (FC) and on spatial working memory by using Radial Arm Morris Water Maze (RAWM). For behavioral studies drugs were administered by intra-hippocampal injections. Results - We demonstrated that a brief 20-min perfusion with soluble oligomeric forms of recombinant Tau 4R/2N before a strong theta-burst stimulation markedly impaired LTP with an IC50 of 0.19 μg/ml. Behavioral evaluation of memory showed that intra-hippocampal administration of oTau 4R/2N markedly reduced contextual fear memory without affecting cued fear memory. oTau also impaired RAWM performance since threated animals made a higher number of errors compared to controls, confirming the oTau-induced an impairment of short-term spatial memory. Since oTau can be found in AD-brain derived preparations, we evaluated whether AD-Tau might affect LTP and memory. We confirmed that animals treated with AD-Tau showed an impairment of LTP, fear and spatial memory. Conclusions – Here we provided novel evidence that exogenous oligomeric recombinant oTau and AD-Tau cause synaptic dysfunction and memory loss. These effects have a very fast onset as they are present within a few minutes from the application of the oligomers. These findings improve our knowledge in AD pathogenesis and might be useful to find new effective strategy for developing therapeutics against AD and other tauopathies.