P2-382: A Tau kinase inhibitor protects hippocampal synapses despite of insoluble Tau accumulation

Abstract

A better understanding of the cellular and molecular pathomechanisms of Alzheimer′s disease (AD) is a prerequisite for the development of efficient treatments. We have used a novel assay system based on virus-infected organotypic hippocampal slice cultures that replicates key aspects of tau-driven AD pathology in an authentic CNS environment. Human tau (0N4R/P301L), when expressed in pyramidal neurons of hippocampal slice cultures, was increasingly phosphorylated at several disease-relevant epitopes, leading to progressive neuronal dystrophy and formation of RIPA-insoluble tau. AD-like tau hyperphosphorylation was reduced by the tau kinase inhibitors lithium as well as SRN 003–556, but RIPA-insoluble tau accumulated regardless of reduced tau phosphorylation. Moreover, we obtained evidence that synapse pathology, assessed by two markers for synaptic vesicles, preceded axon and cell body degeneration which is in line with previous in vivo observations. Specifically SRN 003–556, a kinase inhibitor that may partially inhibit multiple tau kinases, but not lithium was able to protect hippocampal neurons from synaptic damage that was presumably caused by a toxic soluble tau fraction. Synapse protection correlated with reduced neurodegeneration observed at later stages. These data provide first mechanistic insights towards the functional benefits of tau kinase inhibition that have been observed in vivo. The ex vivo model system of hippocampal tau pathology described here may facilitate the identification of drug candidates, in particular kinase inhibitors, and help to identify modulators of tau toxicity in hippocampal neurons.