A new therapeutic approach to Tauopathies: targeting presynaptic tau with antisense oligonucleotides to Synaptogyrin‐3

Abstract

AbstractBackgroundThe protein Tau is central to several neurodegenerative disorders (“tauopathies”). “Tau‐tangles” (aggregations of the Tau protein) are a key hallmark of Alzheimer’s and many other diseases and Tau‐protein is mutated in several forms of dementia. In all these conditions, Tau causes complex, multifactorial defects in neurons that lead to cognitive decline. Under normal conditions, Tau is attached to axonal microtubules, but under pathogenic conditions it detaches and spreads throughout the neuron, including synapses. Work from my lab indicated that when Tau is present at pre‐synaptic terminals it binds to and clusters synaptic vesicles and identified Synaptogyrin‐3 as a physical interactor of Tau. My lab demonstrated that the partial loss of Synaptogyrin‐3 (Syngr3) restores working memory and rescues synaptic degeneration in mice that express pathogenic P301S Tau (“PS19”), a well‐accepted model for tauopathy that recapitulates features seen in patients, including synaptic loss, neuroinflammation and cognitive decline. Partial (and complete) loss of Syngr3 is benign in mice and fruit flies. Based on this, we pursued a radical alternative and innovative approach, supported by strong pre‐clinical data, to tackle Tau‐induced cognitive decline.MethodWe designed and synthetized oligonucleotides covering the whole Syngr3 transcript, and tested their activity in Neuro2A cells and primary cortical murine neurons in transfection and unassisted uptake conditions.ResultThrough this screen we found several active molecules, that were able to significantly downregulate Syngr3 transcript and protein levels. To find the best candidates, we performed dose‐response curves and time course evaluations in primary murine neurons, and we found several molecules that targeted different regions of the Syngr3 transcript with good activity, potency, and no evident toxic effects.ConclusionWe found several molecules that induce an effective and sustained reduction of Syngr3 expression. As part of the pre‐clinical evaluation, these molecules will be tested in vivo in PK/PD and acute toxicity studies in WT mice, to determine the best administration dosage and therapeutic window. Finally, we will evaluate the effect of our best candidates in a therapeutic setting, treating PS19 tau mice to assess if the acute removal of the protein can alleviate presynaptic tau toxicity and revert tau induced synaptic and cognitive defects.