Extracellular oligomeric tau inhibits synaptic plasticity and memory

Tau protein has been shown to play a toxic role in Alzheimer's disease. However, there is no clear-cut demonstration of whether and how tau impairs synaptic function and memory, a pre-requisite for a molecule playing a key role in the disease. Here, we show that soluble oligomeric tau, a recently described form that can be released in the extracellular space, is detectable in human cerebrospinal fluid and the release of these tau forms can be enhanced upon neuronal activity. Infusion of a mixed preparation containing tau oligomers and monomers either synthetically produced or isolated from Alzheimer´s disease patient cortex disrupt both hippocampal synaptic plasticity and associative fear memory. On the contrary, monomeric recombinant tau produces no detrimental effects. This impairment is associated with mechanisms involving gene transcription machinery relevant to memory formation and does not require the association with increased Beta-amyloid peptide production or modified Amyloid Precursor Protein cleavage machinery. Taken together, these findings suggest that extracellular tau oligomers can be responsible for the discrete changes in synaptic function underlying the earliest subtle amnesic symptoms in Alzheimer´s disease. Therefore, our work highlights a new mechanism for tau-induced toxicity both in Alzheimer's disease and other tauopathies.