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 G alpha q and PI3K/Akt/mTOR pathways upon G alpha i 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.
[1]Shandong Second Med Univ, Sch Basic Med Sci, Weifang 261042, Shandong, Peoples R China.
[2]Jining Med Univ, Neurobiol Inst, Jining 272067, Shandong, Peoples R China.
[3]Shandong Second Med Univ, Sch Clin Med, Weifang 261042, Shandong, Peoples R China.
[4]Univ Warwick, Warwick Med Sch, Div Biomed Sci, Coventry CV4 7AL, England.
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