Study on YIPF2 Inhibitors Improving Oligodendrocyte Susceptibility to Human Islet Amyloid Polypeptide

With the dramatic increase in global diabetes prevalence, the harm of diabetes complications is becoming increasingly prominent. Among them, Diabetic Encephalopathy (DE), as the most common complication in type 2 diabetes, severely affects patients’ quality of life and social health status. Despite continuous improvement in medical conditions and increased survival rates of diabetic patients, many patients experience physical disabilities due to related complications. In recent years, researchers have turned their attention to oligodendrocytes (OLs) to explore the pathogenesis of DE.

Research Background

Studies have indicated that abnormal secretion of Human Islet Amyloid Polypeptide (HIAPP) is an important pathological basis for DE. This study was conducted by a team from the Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, including Nan Zhang, Xiaoying Ma, Xinyu He, Yaxin Zhang, Xin Guo, Zhiyuan Shen, Xiaosu Guo, Dancan Zhang, Shujuan Tian, Xiaowei Ma, and Yuanxing. They aimed to explore the potential impact of HIAPP in the pathogenesis of DE. Research methods included using brain magnetic resonance imaging (MRI) to assess white matter damage and comparing cognitive scores with HIAPP levels in the serum of type 2 diabetes patients.

Research Source and Methods

The article was published in the journal “Neurosci. Bull.”, with DOI 10.1007/s12264-024-01263-6, from institutions including the First Hospital of Hebei Medical University, Hebei Neurology Technology Innovation Center, and School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology.

Through brain MRI and cognitive ability assessments of patients with type 2 diabetes, it was found that serum HIAPP concentration was significantly positively correlated with white matter damage area and negatively correlated with cognitive scores. In vitro experiments showed that oligodendrocytes were more susceptible to acidosis under exogenous HIAPP stimulation compared to neurons. Furthermore, differential proteomics analysis revealed that yeast Rab GTPase interaction protein 2 (YIPF2) might be an important target affecting the transfer of CD147 to the cell membrane. The study generated YIPF2-CKO mice and siYIPF2 cells, demonstrating that YIPF2 inhibition significantly improved oligodendrocyte resistance to HIAPP-induced acidosis and cognitive dysfunction in DE model mice.

Research Results

HIAPP interferes with oligodendrocytes by intervening in the binding process between the lactate transporter (MCT) 1 and its auxiliary protein CD147, but does not affect the binding of MCT2 and its auxiliary protein gp70. By inhibiting YIPF2, the transport of CD147 to the cell membrane was increased, optimizing the binding of MCT1 and CD147, and potentially alleviating HIAPP-induced acidosis and subsequent DE-related demyelination.

Research Conclusions and Significance

This study demonstrates that inhibiting YIPF2 can enhance oligodendrocyte resistance to Human Islet Amyloid Polypeptide (HIAPP) and provide potential therapeutic targets for DE. These findings not only elucidate the role of MCTs in oligodendrocyte susceptibility to HIAPP but also identify YIPF2 as a promising therapeutic target, potentially opening new avenues for the prevention and treatment of DE.