2. Academic Validation
  3. Apelin Receptor Homodimerisation Inhibits Hippocampal Neuronal Autophagy via G Protein-Dependent Signalling in Vascular Dementia

Apelin Receptor Homodimerisation Inhibits Hippocampal Neuronal Autophagy via G Protein-Dependent Signalling in Vascular Dementia

  • Mol Neurobiol. 2024 Jul 23. doi: 10.1007/s12035-024-04383-2.
Xin Cai # 1,  Shujuan Hu # 1,  Wenkai Liu 1,  Yue Yin 1,  Yunlu Jiang 2,  Yixiang Wang 3,  Bowen Lu 3,  Yuliang Wang 1,  Dexiu Wang # 4,  Jing Chen # 5 6
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, 261042, P.R. China.
  • 2 Neurobiology Institute, Jining Medical University, Jining, Shandong, 272067, P.R. China.
  • 3 School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, 261042, P.R. China.
  • 4 School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, 261042, P.R. China. wangdx0523@163.com.
  • 5 Neurobiology Institute, Jining Medical University, Jining, Shandong, 272067, P.R. China. Jing.Chen@warwick.ac.uk.
  • 6 Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK. Jing.Chen@warwick.ac.uk.
  • # Contributed equally.
PMID: 39042220 DOI: 10.1007/s12035-024-04383-2
Abstract

Vascular dementia (VD), a progressive vascular cognitive impairment, is characterised by the presence of cerebral hypoperfusion, increased blood-brain barrier permeability, and white matter lesions. Although current treatment strategies primarily focus on risk factors such as hypertension, diabetes, and heart disease, efficient and targeted therapies are lacking and the underlying mechanisms of VD remain unclear. We previously discovered that Apelin receptors (APJ), which are G protein-coupled receptors (GPCRs), can homodimerize and generate signals that are distinct from those of APJ monomers in VD rats. Apelin-13 reduces the level of APJ homodimers and leads to the proliferation of endogenous neural stem cells in the hippocampal dentate gyrus area, suggesting that it has a neuroprotective role. In this study, we established a rat and cellular oxygen-glucose deprivation/reoxygenation VD model to investigate the impact of APJ homodimerisation on Autophagy. We found that APJ homodimers protect against VD by inhibiting Autophagy through the Gαq and PI3K/Akt/mTOR pathways upon Gαi signalling, both in vivo and in vitro. This discovery provides a promising therapeutic target for chronic cerebral ischaemia-reperfusion diseases and an experimental foundation for the development of drugs that target APJ homodimers.

Keywords

Apelin receptor; Autophagy; Drug target; G protein-coupled receptor; Homodimer; Vascular dementia.

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