Authors: Bowen Zhang, Changjie Shi, Jiayi Zhao, Qiuhong Hua, Houchun Zhang, Hailin Gao, Yuanyuan Qian, Jiaxue Cha, Jing Li, Jiayao Chen, Tae-Hyung Kim, Jianhuang Xue, Yujun Hou, and Ru Zhang
Exploration, 02 April 2026
Maestro MEA recordings reveal genotype-dependent neuronal network dysfunction in APOE4 cerebral organoid models of Alzheimer’s disease.
Alzheimer’s disease is associated with complex interactions between genetic risk factors, neuroinflammation, and neuronal dysfunction, but the mechanisms linking these processes are not fully understood. In this study, researchers investigated how loss of the RNA-binding protein RBFOX1 influences Alzheimer’s disease pathology in human cerebral organoids carrying either the APOE3 or APOE4 allele, a major genetic risk factor for late-onset Alzheimer’s disease.
Using CRISPR/Cas9 gene editing, the team generated RBFOX1 knockout cerebral organoids and evaluated how RBFOX1 dysfunction altered neuronal and microglial phenotypes. Functional electrophysiological recordings performed on Axion Biosystems’ Maestro MEA platform revealed pronounced neuronal network dysfunction specifically in APOE4_RBFOX1-KO organoids. These organoids exhibited reduced activity across multiple network metrics, including spike rate, mean firing rate, bursting behavior, synchrony, and network variability—findings consistent with established Alzheimer’s disease pathophysiology.
Notably, the researchers observed minimal functional differences between APOE3 and APOE3_RBFOX1-KO organoids, suggesting that RBFOX1 dysfunction may selectively exacerbate disease-relevant phenotypes in the context of APOE4 genetic risk. Together, these findings highlight how organoid-based electrophysiology can uncover genotype-dependent mechanisms of neurodegeneration and provide new insight into how RBFOX1 contributes to Alzheimer’s disease progression.
