Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation

Pablo Largo-Barrientos, Nno Apostolo, Eline Creemers, Zsuzsanna Callaerts-Vegh, Jef Swerts, Caitlin Davies, Joseph McInnes, Keimpe Wierda, Bart De Strooper, Tara Spires-Jones, Joris de Wit, Valerie Uytterhoeven, Patrik Verstreken

Research output: Contribution to journalArticlepeer-review

Abstract

Tau is a major driver of neurodegeneration and is implicated in over 20 diseases. Tauopathies are characterized by synaptic loss and neuroinflammation, but it is unclear if these pathological events are causally linked. Tau binds to Synaptogyrin-3 on synaptic vesicles. Here, we interfered with this function to determine the role of pathogenic Tau at pre-synaptic terminals. We show that heterozygous knockout of synaptogyrin-3 is benign in mice but strongly rescues mutant Tau-induced defects in long-term synaptic plasticity and working memory. It also significantly rescues the pre- and post-synaptic loss caused by mutant Tau. However, Tau-induced neuroinflammation remains clearly upregulated when we remove the expression of one allele of synaptogyrin-3. Hence neuroinflammation is not sufficient to cause synaptic loss, and these processes are separately induced in response to mutant Tau. In addition, the pre-synaptic defects caused by mutant Tau are enough to drive defects in cognitive tasks.
Original languageEnglish
Pages (from-to)1-11.e1-e5
Number of pages16
JournalNeuron
VolumeN/A
Early online date19 Jan 2021
DOIs
Publication statusE-pub ahead of print - 19 Jan 2021

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