Inhibition of YIPF2 Improves the Vulnerability of Oligodendrocytes to Human Islet Amyloid Polypeptide
Nan Zhang1,2 · Xiaoying Ma1 · Xinyu He3 · Yaxin Zhang2,4 · Xin Guo2,4 · Zhiyuan Shen2,4 · Xiaosu Guo2,4 · Danshen Zhang3 · Shujuan Tian2,4 · Xiaowei Ma2,4 · Yuan Xing2,41 Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China
2 Neuromedical Technology Innovation Center of Hebei Province, Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China
3 College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050000, China
4 Department of Neurology, Hebei Hospital, Xuanwu Hospital of Capital Medical University, Shijiazhuang 050000, China
Abstract
Excessive secretion of human islet amyloid polypeptide (hIAPP) is an important pathological basis of diabetic encephalopathy (DE). In this study, we aimed to investigate the potential implications of hIAPP in DE pathogenesis. Brain magnetic resonance imaging and cognitive scales were applied to evaluate white matter damage and cognitive function. We found that the concentration of serum hIAPP was positively correlated with white matter damage but negatively correlated with cognitive scores in patients with type 2 diabetes mellitus. In vitro assays revealed that oligodendrocytes, compared with neurons, were more prone to acidosis under exogenous hIAPP stimulation. Moreover, western blotting and co-immunoprecipitation indicated that hIAPP interfered with the binding process of monocarboxylate transporter (MCT)1 to its accessory protein CD147 but had no effect on the binding of MCT2 to its accessory protein gp70. Proteomic differential analysis of proteins co-immunoprecipitated with CD147 in oligodendrocytes revealed Yeast Rab GTPase-Interacting protein 2 (YIPF2, which modulates the transfer of CD147 to the cell membrane) as a significant target. Furthermore, YIPF2 inhibition significantly improved hIAPP-induced acidosis in oligodendrocytes and alleviated cognitive dysfunction in DE model mice. These findings suggest that increased CD147 translocation by inhibition of YIPF2 optimizes MCT1 and CD147 binding, potentially ameliorating hIAPP-induced acidosis and the consequent DE-related demyelination.
Keywords
Diabetic encephalopathy · Human islet amyloid polypeptide · Oligodendrocytes · Yeast Rab GTPase-interacting protein 2 · Monocarboxylate transporters · CD147
