Liang Shi-Yu, Li Ling-Jie, Huang Ya-Ru, Zhu Jie, Cui Fang, Du Xiao-Yu, Zhang Lun, Jia Ying-Bo, Hou Sheng-Jie, Niu Xiao-Yun, Yang Jin-Ju, Lu Shuai, Liu Rui-Tian
State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Int J Mol Sci. 2025 May 2;26(9):4343. doi: 10.3390/ijms26094343.
Neuronal apoptosis is an early and critical pathological hallmark of many chronic neurodegenerative diseases, often occurring silently long before the appearance of overt clinical symptoms. In this study, we engineered astrocytes utilizing a dual-biomarker recognition synNotch system (dual-synNotch). This system is designed to specifically identify neuronal apoptosis through the 'AND Gate' activation mechanism, which is triggered by the simultaneous sensing of the apoptotic signal phosphatidylserine (PS) and the neuronal signal ganglioside Gt1b. Upon detection of these neuronal apoptotic signals, the synNotch receptors are activated, inducing the expression of two key molecules: secreted Gaussia luciferase (GLuc), a highly detectable reporter that can cross the blood-brain barrier (BBB), and brain-derived neurotrophic factor (BDNF), a neuroprotective molecule that promotes neuronal survival by inhibiting apoptosis and enhancing memory and cognitive function. This engineered system effectively converts and amplifies early, imperceptible neuronal apoptotic signals into detectable outputs, enabling convenient in vitro monitoring and diagnosis. Therefore, it represents a promising strategy for the early detection and intervention of neurodegenerative diseases associated with neuronal apoptosis.
神经元凋亡是许多慢性神经退行性疾病早期的关键病理特征，通常在明显临床症状出现之前很久就悄然发生。在本研究中，我们利用双生物标志物识别合成Notch系统（双合成Notch）对星形胶质细胞进行了工程改造。该系统旨在通过“与门”激活机制特异性识别神经元凋亡，该机制由同时感知凋亡信号磷脂酰丝氨酸（PS）和神经元信号神经节苷脂Gt1b触发。一旦检测到这些神经元凋亡信号，合成Notch受体就会被激活，诱导两种关键分子的表达：分泌型高斯荧光素酶（GLuc），一种可高度检测的报告分子，能够穿过血脑屏障（BBB）；以及脑源性神经营养因子（BDNF），一种神经保护分子，通过抑制凋亡和增强记忆及认知功能来促进神经元存活。这种工程系统有效地将早期难以察觉的神经元凋亡信号转化并放大为可检测的输出，便于进行体外监测和诊断。因此，它代表了一种用于早期检测和干预与神经元凋亡相关的神经退行性疾病的有前景的策略。
