OVEREXPRESSION OF SHATI/NAT8L IN THE HIPPOCAMPUS AMELIORATES COGNITIVE DYSFUNCTION IN MODEL MICE WITH ALZHEIMER’ S DISEASE

Abstract Background Shati/Nat8l was identified as an upregulated molecule in the nucleus accumbens of mice with repeated administration of methamphetamine. We have reported the role of this molecule in psychiatric disorders such as depression as well as drug dependence. Aims & Objectives The purpose of this study was to investigate the role of Shati/Nat8l in cognitive function. For this purpose, we evaluated the cognitive function of the mice with hippocampus-specific knockdown of Shati/Nat8l on wildtype and Alzheimer’ s disease (AD) model mice with hippocampus-specific overexpression of Shati/Nat8l. Method Hippocampus-specific Shati/Nat8l knockdown mice were generated by local microinjection of an adeno- associated virus (AAV) vector for the Cre expression into the hippocampus of Shati-flox mice (7 weeks old, male). AD model mice with hippocampus-specific overexpression of Shati/Nat8l were generated by local microinjection of AAV vectors for expression Shati/Nat8l into the hippocampus of 5xFAD mice (6 weeks old, male), which overproduces amyloid-β. These mice were used for experiments after 4 weeks from AAV vector administration. Results Mice with hippocampus-specific Shati/Nat8l knockdown showed cognitive dysfunction in a novel object recognition test. In the acute slices of these mice, a marked suppression of synaptic long-term potentiation in the CA1 region induced by θ-burst stimulation of the hippocampal Schaffer's lateral branch was observed. 5xFAD mice exhibited decreased hippocampal expression of Shati/Nat8l and cognitive dysfunction. Hippocampus-specific overexpression of Shati/Nat8l improved cognitive dysfunction in 5xFAD mice. In these mice, no alterations of amyloid β accumulation or neurodegeneration in the hippocampus were observed, whereas the expression of BDNF, a neurotrophic factor, was increased. Discussion & Conclusion These results indicate that hippocampal Shati/Nat8l is important for cognitive function. For AD pathology with the reduction of hippocampal Shati/Nat8l, genetic supplementation of Shati/Nat8l could be an effective therapeutic strategy for the treatment of cognitive dysfunction.