Soluble tau aggregates inhibit synaptic long-term depression and amyloid β-facilitated LTD in vivo

Soluble synaptotoxic aggregates of the main pathological proteins of Alzheimer's disease, amyloid beta-protein (A beta) and tau, have rapid and potent inhibitory effects on long-term potentiation (LTP). Although the promotion of synaptic weakening mechanisms, including long-term depression (LTD), is posited to mediate LTP inhibition by A beta, little is known regarding the action of exogenous tau on LTD. The present study examined the ability of different assemblies of full-length human tau to affect LTD in the dorsal hippocampus of the anaesthetized rat. Unlike A beta, intracerebroventricular injection of soluble aggregates of tau (S tau As), but not monomers or fibrils, potently increased the threshold for LTD induction in a manner that required cellular prion protein. However, MTEP, an antagonist of the putative prion protein coreceptor metabotropic glutamate receptor 5, did not prevent the disruption of synaptic plasticity by S tau As. In contrast, systemic treatment with Ro 25-6981, a selective antagonist at GluN2B subunit-containing NMDA receptors, reduced STA-mediated inhibition of LTD, but not LTP. Intriguingly, S tau As completely blocked A beta-facilitated LTD, whereas a subthreshold dose of S tau As facilitated A beta-mediated inhibition of LTP. Overall, these findings support the importance of cellular prion protein in mediating a range of, sometimes opposing, actions of soluble A beta and tau aggregates with different effector mechanisms on synaptic plasticity.