ABHD6 inhibition alleviates memory deficits in an Alzheimer's disease mouse model

Abstract

Abstract Synaptic dysfunction plays a crucial role in the pathogenesis of Alzheimer's disease (AD). α/β-hydrolase domain-containing 6 (ABHD6) plays a critical role in the regulation of synaptic plasticity, and ABHD6 inhibition has shown potential therapeutic value in several neurological disorders. However, the role of ABHD6 in AD has not been fully defined. In this study, we demonstrated that Adeno-associated virus (AAV)-mediated ABHD6 inhibition in hippocampal neurons attenuated synaptic dysfunction and memory impairment of APPswPS1dE9 (APP/PS1) mice, while it didn't affect the amyloid-beta (Aβ) levels and neuroinflammtion in the brains. In addition, intraperitoneal injection of wwl70, a specific inhibitor of ABHD6, improved the synaptic plasticity and memory function in APP/PS1 mice. Furthermore, wwl70 significantly decreased the Aβ levels and neuroinflammtion in the hippocampus of AD mice, which indicated that wwl70 might exert the neuropreotctive effects not only by neuronal ABHD6 inhibition. In conclusion, for the first time our data has shown that ABHD6 inhibition might be a promising strategy for AD treatment, and wwl70 is a potential candidate for AD drug development pipeline.