Divergent disruptive effects of soluble recombinant tau assemblies on synaptic plasticity in vivo.

Abstract

Neurofibrillary tangles (NFTs), composed of tau protein fibrils, together with brain inflammation and synaptic loss, are neuropathological hallmarks of several neurodegenerative diseases, including Alzheimer's disease. Compared with tau fibrils, more water-soluble assemblies of either recombinant or patient-derived tau have been reported to exert relatively potent rapid synaptotoxic effects, including inhibition of synaptic long-term potentiation (LTP) in the hippocampus. Less is known regarding the action of exogenous tau soluble assemblies on the opposite form of synaptic plasticity, long-term depression (LTD). We compared the synaptic plasticity actions of two relatively standard preparations of soluble recombinant tau assemblies, (i) fibril-derived soluble sonicated tau aggregates (SτAs) and (ii) oligomer-enriched tau (oTau) prepared from monomers. Consistent with previous findings, intracerebroventricular injections of either SτAs or oTau acutely inhibited high-frequency stimulation-induced LTP at CA3-to-CA1 synapses in the anaesthetized rat hippocampus. However, LTP inhibition by oTau, but not SτAs, was prevented by co-injection with the conformational anti-tau monoclonal antibody, TOMA1. Furthermore, in contrast to SτAs, which inhibited LTD, injection of oTau potently facilitated LTD, decreasing the threshold for LTD induction by low-frequency stimulation. To test the role of pro-inflammatory cytokines in mediating the disruptive effects of the two forms of soluble tau on synaptic plasticity we pre-injected etanercept, a decoy receptor for tumor necrosis factor alpha (TNFα). Etanercept reduced the disruption of synaptic plasticity by oTau but not by SτAs. Moreover, injection of exogenous TNFα mimicked the facilitation of LTD by oTau, consistent with a role of this pro-inflammatory cytokine in LTD facilitation.These data provide evidence that preparations of soluble tau containing either monomer- or fibril-derived assemblies disrupt LTP and LTD via different mechanisms. Intriguingly, when oTau and SτAs were applied together, LTD block predominated. Thus, if similar synaptotoxic soluble tau assemblies are present together later during the disease process, as seems likely, inhibition of synaptic weakening processes is predicted to predominate. Equally, reducing TNFα would be expected to be more effective when the monomer-derived soluble tau assemblies are the dominant synaptotoxic species. We conclude that oTau and SτAs provide useful means to explore ways of targeting different synaptotoxic soluble tau species in tauopathies.