2. Academic Validation
  3. Wwl70-induced ABHD6 inhibition attenuates memory deficits and pathological phenotypes in APPswe/PS1dE9 mice

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

  • Pharmacol Res. 2023 Jul 20;106864. doi: 10.1016/j.phrs.2023.106864.
Zhiwei Xue 1,  Lei Ye 2,  Jianwei Ge 2,  Zhen Lan 3,  Xinxin Zou 4,  Chenglu Mao 1,  Xinyu Bao 1,  Linjie Yu 1,  Yun Xu 5,  Xiaolei Zhu 6
Affiliations

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, 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.
  • 3 Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: [email protected].
  • 4 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; Department of Neurology, Drum Tower Hospital of Xuzhou Medical University, Nanjing, Jiangsu, China.
  • 6 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: [email protected].
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; Aβ(1-42) (PubChem CID: 57339251); Wwl70 (PubChem CID: 17759121); amyloid-beta; memory functions; microglia; synaptic plasticity.

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