Abstract
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).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.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.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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.