CircLPAR1/miR-212-3p/ZNF217 feedback loop promotes amyloid β-induced neuronal injury in Alzheimer's Disease.

BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognition and language impairment. CircRNA lysophosphatidic acid receptor 1 (circLPAR1) was found to be increased in AD patients, however, the potential role of circLPAR1 in AD process remains unclear.

METHODS: Beta-amyloid (Aβ) 25-35-stimulated CHP-212 and IMR-32 cells were used to perform expression and function analyses. The expression of genes and proteins was determined by qRT-PCR and Western blot. Cell proliferation and apoptosis were analyzed using cell counting kit-8 (CCK-8) assay, flow cytometry, and Western blot, respectively. ELISA analysis was used to detect the levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). The levels of reactive oxygen species (ROS), lactate dehydrogenase (LDH) and superoxide dismutase (SOD) were detected using commercial kits. The direct interactions between miR-212-3p and ZNF217 (Zinc finger protein 217) or circLPAR1 was verified using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays.

RESULTS: CircLPAR1 was highly expressed in AD patients and Aβ25-35-stimulated CHP-212 and IMR-32 cells. Knockdown of circLPAR1 suppressed Aβ25-35-induced neuronal apoptosis, inflammation, and oxidative stress. Mechanistically, circLPAR1 competitively bound to miR-212-3p to elevate its target ZNF217. Rescue experiments suggested that miR-212-3p inhibition reversed circLPAR1 silencing-evoked inhibition on neuronal injury under Aβ25-35 stimulation. Moreover, miR-212-3p re-expression reduced Aβ25-35-induced neuronal apoptosis, inflammation, and oxidative stress, which were abolished by ZNF217 up-regulation.

CONCLUSION: CircLPAR1 promotes Aβ25-35-induced apoptosis, inflammation, and oxidative stress via miR-212-3p/ZNF217 axis, suggesting a new insight into the pathogenesis of AD.