Wwl70-induced ABHD6 inhibition attenuates memory deficits and pathological phenotypes in APPswe/PS1dE9 mice

Zhiwei Xue; Lei Ye; Jianwei Ge; Zhen Lan; Xinxin Zou; Chenglu Mao; Xinyu Bao; Linjie Yu; Yun Xu; Xiaolei Zhu

doi:10.1016/j.phrs.2023.106864

Wwl70-induced ABHD6 inhibition attenuates memory deficits and pathological phenotypes in APPswe/PS1dE9 mice

Pharmacol Res. 2023 Aug:194:106864. doi: 10.1016/j.phrs.2023.106864. Epub 2023 Jul 20.

Authors

Zhiwei Xue¹, Lei Ye¹, Jianwei Ge¹, Zhen Lan², Xinxin Zou³, Chenglu Mao¹, Xinyu Bao¹, Linjie Yu¹, Yun Xu⁴, Xiaolei Zhu⁵

Affiliations

¹ Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, Jiangsu, China.
² Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
³ Department of Neurology, Drum Tower Hospital of Xuzhou Medical University, Nanjing, Jiangsu, China.
⁴ Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, Jiangsu, China; Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Department of Neurology, Drum Tower Hospital of Xuzhou Medical University, Nanjing, Jiangsu, China.
⁵ Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, Jiangsu, China; Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: zhuquelee@126.com.

PMID: 37480972
DOI: 10.1016/j.phrs.2023.106864

Abstract

Synaptic dysfunction plays a crucial role in the pathogenesis of Alzheimer's disease (AD). α/β-hydrolase domain-containing 6 (ABHD6) contributes to synaptic dysfunctions, and ABHD6 inhibition has shown potential therapeutic value in 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 shRNA targeting ABHD6 in hippocampal neurons attenuated synaptic dysfunction and memory impairment of APPswe/PS1dE9 (APP/PS1) mice, while it didn't affect the amyloid-beta (Aβ) levels and neuroinflammation in the brains. In addition, intraperitoneal injection of wwl70, a specific inhibitor of ABHD6, improved synaptic plasticity and memory function in APP/PS1 mice, which might attribute to the activation of endogenous cannabinoid signaling. Furthermore, wwl70 significantly decreased the Aβ levels and neuroinflammation in the hippocampus of AD mice, and enhanced Aβ phagocytized by microglia. In conclusion, for the first time our data have shown that ABHD6 inhibition might be a promising strategy for AD treatment, and wwl70 is a potential candidate for AD drug development pipeline.

Keywords: ABHD6; AM251 (PubChem CID: 2125); AM630 (PubChem CID: 4302963); Alzheimer's disease; Amyloid-beta; Aβ(1–42) (PubChem CID: 57339251); Memory functions; Microglia; Synaptic plasticity; Wwl70 (PubChem CID: 17759121).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / genetics
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Animals
Disease Models, Animal
Hydrolases*
Memory Disorders / drug therapy
Mice
Mice, Transgenic
Monoacylglycerol Lipases
Neuroinflammatory Diseases

Substances

ABHD6 protein, mouse
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Hydrolases
Monoacylglycerol Lipases
N-methyl-N-((3-(4-pyridinyl)phenyl)methyl)-4'-(aminocarbonyl)(1,1'-biphenyl)-4-yl ester, carbamic acid