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

Abstract

AbstractBackgroundSynaptic dysfunction plays a crucial role in the pathogenesis of Alzheimer’s disease (AD). α/β‐hydrolase domain‐containing 6 (ABHD6) inhibition has shown potential therapeutic values in several neurological disorders. However, the role of ABHD6 in AD has not been fully defined.MethodAdeno‐associated virus (AAV) mediated shRNA targeting ABHD6 (AAV‐sh‐ABHD6) was slowly injected into bilateral hippocampus of APPswPS1dE9 (APP/PS1) mice, or ABHD6 inhibitor wwl70 was intraperitoneally injected into APP/PS1 mice for 30 days. The behavioral tests including Open field, New object recognition, Y maze, Morris water maze and Fear condition were performed. Synaptic transmission, dendritic spine density and synaptic proteins levels were investigated by electrophysiological tests, Golgi staining and western blot respectively. The protein levels of amyloid β peptide (Aβ), GFAP and Iba1 were determined by Immunostaining.ResultThe expression of ABHD6 was significantly increased in the hippocampus of APP/PS1 mice. AAV‐sh‐ABHD6 treatment attenuated synaptic dysfunction and memory impairment of APP/PS1 mice, while it didn’t affect the Aβ levels and neuroinflammation in the brains. In addition, intraperitoneal injection of wwl70 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.ConclusionWe demonstrate firstly that ABHD6 contributes to the memory impairment in AD, and ABHD6 inhibition enhances synaptic plasticity and memory functions in APP/PS1 mice, indicating that ABHD6 inhibition is a promising therapeutic strategy for AD treatment.