Activation of chaperone-mediated autophagy exerting neuroprotection effect on intracerebral hemorrhage-induced neuronal injury by targeting Lamp2a.

Intracerebral hemorrhage (ICH) is a common and devastating type of stroke, marked by significant morbidity and a grim prognosis. The inflammation cascade triggered by astrocytes plays a critical role in secondary brain injury (SBI) following ICH, leading to detrimental effects such as cell death. However, effective intervention strategies are currently lacking. This study aims to investigate the role of the astrocyte cascade reaction following ICH and identify potential intervention targets. Utilizing the GSE216607 and GSE206971 databases for analysis, we established a mouse autologous blood model. Firstly, our research revealed a significant activation of the autophagy pathway following intracerebral hemorrhage (ICH), with a notable upregulation of Lamp2a, a key factor in chaperone-mediated autophagy (CMA), primarily localized in astrocytes. Additionally, the downregulation of Lamp2a resulted in a significant augmentation of A1 reactive astrocytes, concomitant with a reduction in myelin coverage area, heightened neuronal injury, exacerbated motor and sensory deficits, and diminished neurological scores after ICH in mice. Conversely, CA77.1, an activator of CMA, could reverse ICH-induced augmentation of A1 reactive astrocytes, myelin damage, neuronal death, and neurobehavioral disorders. In conclusion, the activation of astrocyte CMA following ICH can exert neuroprotective effects. Lamp2a represents a promising therapeutic target for post-ICH treatment.