Synaptic tau and synaptogyrin-3 are promising targets to tackle tauopathies.

BACKGROUND: Different pathogenic conditions (Alzheimer's disease and other tauopathies) induce detachment of Tau protein from microtubules. Detached Tau accumulates at synapses and binds to synaptic vesicle-associated protein Synaptogyrin-3, hampering vesicle mobility and neurotransmitter release (Zhou et al., Nature Communications 2017). Lowering the levels of Synaptogyrin-3 alleviates synaptic dysfunction in fruit flies and mouse primary neurons McInnes et al., Neuron 2018). METHOD: We pursued two strategies to lower Synaptogyrin-3 expression in a tauopathy mouse model (human P301S Tau-expressing mice; "PS19 mouse line"). We generated a synaptogyrin-3 knockout mouse usign CRISPR/Cas9 and crossed it with Tau P301S mice. In paralel, we designed several antisense oligonucleotides (ASOs) against common sequences of mouse and human Synaptogyrin-3. RESULT: We showed that lowering expression of Synaptogyrin-3 is benign in mice, but strongly rescues mutant Tau-induced defects in long-term synaptic plasticity and working memory. We screened several anti-Synaptogyrin-3 ASOs in vitro and selected the most effective one to further study its effects in vivo. CONCLUSION: Lowering Synaptogyrin-3 is safe and sufficient to prevent cognitive decline in Tau P301S mice. Further research will determine the therapeutic potential of interfering with the interaction of Tau and Synaptogyrin-3 in the context of tauopathies.

Publication year:2021

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