Tauopathies (that include Alzheimer’s disease) are characterized by defects in the microtubule-associated protein Tau. This reduces the affinity of Tau to bind microtubules and increases the levels of soluble detached Tau in neurons. Previous ERC-supported work from my lab showed that pathogenic Tau accumulates at pre-synaptic terminals and clusters synaptic vesicles in mouse and fly animal models and in Alzheimer patient brain samples. This pre-synaptic Tau reduces vesicle mobility and blocks neurotransmitter release (Zhou et al., 2017). The interaction of Tau with synaptic vesicles occurs via the synaptic vesicle-associated protein Synaptogyrin-3. Lowering the levels of Synaptogyrin-3 blocks the ability of Tau to efficiently bind to synaptic vesicles (McInnes et al., 2018). When we remove Synaptogyrin-3 from mice that suffer from tau defects we are able to rescue synaptic plasticity as well as cognitive decline and it prevents the loss of synapses in old mice (Largo-Barrientos et al., 2020). Finally, mice without synaptogyrin-3 do not show overt dysfunction, suggesting Synaptogyrin-3 is a promising therapeutic target to tackle tauopathies. In this project we developed antisense oligonucleotides (ASOs) that are compounds that are able to reduce the expression levels of Synaptogyrin-3. We have tested these ASOs in induced human neurons and show efficacy in vivo in mice. This proof-of-concept work is the first step in testing if targeting Synaptogyrin-3 with an ASO in a therapeutic setting is beneficial to suppress Tau-induced defects. These data feed in to a new biotech start-up that we have built.
