Valerie Uytterhoeven, Belgium
VIB-KU Leuven VIB-KU Leuven Center for Brain & Disease ResearchAuthor Of 1 Presentation
LOSS OF SYNAPTOGYRIN-3 RESCUES TAU-INDUCED MEMORY DEFECTS AND SYNAPTIC LOSS IN THE PRESENCE OF MICROGLIAL ACTIVATION
Abstract
Aims
Tauopathies are characterized by synaptic loss and neuroinflammation, but it is unclear if these pathological events are causally linked. We have previously shown that Tau binds to Synaptogyrin-3 on synaptic vesicles, leading to imapired vesicle mobility and pre-synaptic dysfunction. Here we aim to determine the consequences of preventing the binding of Tau to synaptic vesicles in a tauopathy mouse model, and whether this has any benefits in regard to different aspects of Tau-induced pathology.
Methods
We generated a synaptogyrin-3 knockout mouse line using CRISPR/Cas9 technology. We crossed synaptogyrin-3 knockout mice and human P301S Tau-expressing mice, and evaluated the effect of reducing Synaptogyrin-3 levels on different Tau-induced phenotypes. Given that Synaptogyrin-3 is uniquely present at pre-synaptic terminals, this allows us to decipher the contribution of pre-synaptic Tau to overall Tau-induced pathology.
Results
We show that loss of Synaptogyrin-3 rescues Tau-induced defects in long-term potentiation and working memory. It also significantly rescues the synaptic loss in the stratum lucidum caused by mutant Tau. However, hyper-phosphorylated Tau still accumulates at synapses and Tau-induced neuroinflammation remains clearly upregulated when we remove synaptogyrin-3.
Conclusions
We conclude that neuroinflammation is not sufficient to induce synaptic loss and these processes are separately induced in response to mutant Tau. In addition, the presynaptic defects caused by mutant Tau drive cognitive decline.