TAU OLIGOMERS MEDIATE RIBOSOMAL DYSFUNCTION AT THE SYNAPSE

Abstract

Tau is known to interact with ribosomes both under normal and Alzheimer's disease conditions. We have shown that oligomeric tau, a conformer associated with tau toxicity, impairs ribosomal activity and attenuates nascent protein translation. We hypothesize the tau mediated impairment of ribosome function is a key process in the pathogenesis of Alzheimer's disease and other tauopathies. The impact of tau-mediated impairment of ribosomal function on synaptic proteins was assessed by treating primary neurons with tau oligomers and collecting synaptic fractions. These fractions were analyzed with surface sensing of translation (SUnSET) to determine ribosomal function at the synapse. Changes in the levels and types of mRNA and protein were also determined. The in vitro data was expanded by examining protein translation in rTg4510 tau transgenic mice using an innovative approach of adapting SUnSET in vivo. Protein synthesis as measured by immunohistochemistry and biochemical analysis of synaptosome fractions. Broad neuronal function measures were performed using manganese-enhanced MRI with R1 mapping, a novel MRI approach developed in our laboratory. Cognitive status was evaluated using a battery of behavioral tests. Tau oligomers impaired translation of key synaptic proteins both in primary neurons and rTg4510 mice. Further, tau-mediated impaired protein synthesis in rTg4510 mice was readily detectable by SUnSET. Finally, we identified rescue of broad neuronal function and cognition in tau transgenic when tau transgenic mice were treated with compounds that uncouple the tau-ribosome association. These data suggest that a key pathway contributing to cognitive deficits characteristic of tauopathies such as AD may be tau-mediated impairment of synaptic protein synthesis. Future efforts will focus on identifying and validating therapeutic strategies to rescue dysfunctional synaptic protein synthesis.