FSS in CTE triggers neuronal apoptosis through Piezo1-induced Ca2+ homeostasis disruption

Abstract

The altered cerebrospinal fluid dynamics induced by strenuous competitive sports result in repeated exposure of neurons to abnormal fluid shear stress (FSS). Although the stress intensity did not result in diffuse axonal injury, prolonged stimulation still induced chronic traumatic encephalopathy (CTE), characterized by neuronal dysfunction and apoptosis. However, the mechanism underlying the effects of elevated FSS in axon-intact cells remains unclear. In this study, microfluidic technology was utilized to apply FSS stimulation to depolarized SH-SY5Y cells. Utilizing Ca²⁺ biosensors based on Fluorescence resonance energy transfer technology to detect changes in intracellular calcium concentration ([Ca²⁺]_i) and endoplasmic reticulum Ca²⁺ release. The results indicated that FSS significantly elevate [Ca²⁺]_i during depolarization, enhancing vesicle release in short-term and apoptosis in long-term. The elevation of [Ca²⁺]_i was primarily attributed to extracellular Ca²⁺ influx via Piezo1 channels. Inhibition of Piezo1 activation suppressed aberrant vesicle release and attenuated apoptosis. This study identifies a novel CTE mechanism: FSS disrupts Ca²⁺ homeostasis in depolarized neurons via Piezo1-mediated Ca²⁺ influx, triggering aberrant vesicle release and apoptosis. This mechanism may provide crucial insights for the development of novel strategies to prevent or treat sports-related brain injuries and diseases.