CircMAP2 attenuates synaptic impairment in neurons subjected to cerebral ischaemia/reperfusion injury

BACKGROUND: Acute ischaemic stroke (AIS) is a major cause of disability and mortality worldwide, yet rapid diagnostic tools and effective neuroprotective strategies against ischaemia/reperfusion (I/R) injury postrecanalisation are critically lacking. This study investigates circular RNA derived from the gene of microtubule-associated protein 2 (CircMAP2) as a novel biomarker for AIS and its neuroprotective role in I/R injury. METHODS: CircMAP2 was identified in I/R neurons and exosomes. Its expression was quantified via real-time quantitative reverse transcription PCR in plasma from the healthy control group (n=30) and patients with AIS (n=56), with infarct volumes measured by MRI. Functional studies employed small interfering RNA knockdown and adenoviral overexpression of CircMAP2 in vitro and in vivo, assessing neuronal survival, synaptic integrity by Golgi staining and immunofluorescence and detecting synaptic plasticity-related proteins by western blot analysis. Mechanistic insights were gained through RNA pull-down and transcriptional assays to evaluate interactions with U1 small nuclear ribonucleoprotein (U1 snRNP) and RNA polymerase II. RESULTS: CircMAP2 was significantly upregulated in the peri-infarct and ischaemic core of middle cerebral artery occlusion/reperfusion mice, as well as in AIS patient plasma. Regression analysis linked elevated CircMAP2 levels to larger infarct volumes (p<0.01). While CircMAP2 knockdown exacerbated I/R-induced neuronal damage, its overexpression preserved synaptic structure and reduced injury. Mechanistically, CircMAP2 bound U1 snRNP to stabilise MAP2 messenger RNA, enhancing neuroprotection. CONCLUSIONS: CircMAP2 functions dually as a potential AIS diagnostic biomarker and I/R therapeutic target, regulating MAP2 through U1 snRNP to preserve synapses and reorganise neural circuits, offering combined diagnostic and neuroprotective potential.