Identification of synaptic targets for the treatment of tauopathies

Tau protein is involved in Alzheimer’s disease (AD) and numerous other brain disorders (“tauopathies”). The protein is attached to axonal microtubules, but pathogenic mutations or hyperphosphorylation induce it to detach. The accumulation of Tau at synapses ultimately induces synaptic dysfunction and degeneration. I previously showed that the presynaptic problems provoked by Tau are sufficient to induce cognitive decline, and rescuing the Tau-induced presynapse-specific defects prevents cognitive decline in a tauopathy mouse model. This proof-of-concept suggests that interfering with functions of Tau in a cell-compartment-specific manner (synapses only), rather than bluntly removing the protein altogether, may be an effective strategy to treat tauopathies; however, the exact mode-of-action of Tau at synapses, and effective methodology to target Tau at synaptic compartments remain poorly explored. Here, I will perform a synapse-specific proteomic screen using a well-established mouse model and a genetic screen using validated fly Tau models to identify druggable synaptic targets for the treatment of tauopathy. I will then develop antisense oligonucleotides (ASOs) to 2 of these targets (one target, Crmp, is already identified) and test these in relevant cell and animal models.