Lowering Synaptogyrin‐3 Expression Rescues Tau‐Induced Memory Deficits and Synaptic Loss in the Presence of Microglial Activation

• DOI: 10.1002/alz.064090
• Publication Date: 2022-12-20T15:19:16Z
• Authors: Pablo Largo‐Barri...; Bart De Strooper; Tara L Spires‐Jones; Joris de Wit; Valerie Uytterhoeven; Patrik Verstreken
• Keywords: Tauopathy; Knockout mouse

Abstract Background Tau is implicated in multiple neurodegenerative disorders, including Alzheimer’s disease. Synaptic loss and neuroinflammation are characteristic feautures of tauopathies, but it unclear if these pathological events causally linked whether they relevant for cognitive decline. Mutations and/or hyperphosphorylation leads its accumulation at synapses, where binds to synaptic vesicle‐associated protein Synaptogyrin‐3 resulting clustering vesicles impaired function. Given that uniquely present pre‐synaptic terminals, this allows us decipher the contribution overall Tau‐induced pathology. Method We generated a synaptogyrin‐3 knockout mouse line using CRISPR‐Cas9 technology. −/− +/− mice viable fertile do not show overt phenotypes. bred with human P301S‐expressing (PS19 line) aged offspring. used several techniques, electrophysiology, behavioral tests, immunohistochemistry electron microscopy, determine effects lowering expression tauopathy model. Result found heterozygous P301S was sufficient rescue plasticity working memory defects. Moreover, prevented degeneration markers mice. Interestingly, proliferation activation astrocytes microglia observed P301S; same extent as their littermates. Conclusion Our results indicate induces independently, cause loss. In addition, defects caused by enough drive memory.