Cascade of tau toxicity in inducible hippocampal brain slices and prevention by aggregation inhibitors

Abstract

Mislocalization and aggregation of the axonal protein tau are hallmarks of Alzheimer's disease and other tauopathies. Here, we studied the relationship between tau aggregation, loss of spines and neurons, and reversibility by aggregation inhibitors. To this end we established an in vitro model of tauopathy based on regulatable transgenic hippocampal organotypic slice cultures prepared from mice expressing proaggregant Tau repeat domain with mutation ΔK280 (TauRDΔK). Transgene expression was monitored by a bioluminescence reporter assay. We observed abnormal tau phosphorylation and mislocalization of exogenous and endogenous tau into the somatodendritic compartment. This was paralleled by a reduction of dendritic spines, altered dendritic spine morphology, dysregulation of Ca++ dynamics and elevated activation of microglia. Neurotoxicity was mediated by Caspase-3 activation and correlated with the expression level of proaggregant TauRDΔK. Finally, tau aggregates appeared in areas CA1 and CA3 after three weeks in vitro. Neurodegeneration was relieved by aggregation inhibitors or by switching off transgene expression. Thus the slice culture model is suitable for monitoring the development of tauopathy and the therapeutic benefit of antiaggregation drugs.