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Synaptic tau and synaptogyrin‐3 are promising targets to tackle tauopathies
Author(s) -
LargoBarrientos Pablo,
Uytterhoeven Valerie,
de Wit Joris,
De Strooper Bart,
Verstreken Patrik
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.054187
Subject(s) - tauopathy , neuroscience , context (archaeology) , tau protein , synaptic plasticity , microbiology and biotechnology , synaptic vesicle , biology , alzheimer's disease , neurodegeneration , chemistry , medicine , disease , genetics , vesicle , pathology , membrane , paleontology , receptor
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.