Amyloid β-Induced Redistribution of Transcriptional Factor EB and Lysosomal Dysfunction in Primary Microglial Cells

Xingzhi Guo, Peng Tang, Li Chen, Peng Liu, Chen Hou, Xin Zhang, Yue Liu, Li Chong, Xiaoqing Li, Rui Li

Impaired clearance of Amyloid β (Aβ) by microglia in the brain may be associated with the senile plaque formation, a pathological hallmark relevant to Alzheimer's disease. Microglial cells in the brain are not able to efficiently degrade Aβ, suggesting that microglial lysosome impairment may occur. However, the mechanism of Aβ-induced impairment of microglia remains poorly understood. We observed the effects of Aβ on the trafficking of nuclear transcriptional factor EB (TFEB), a master regulator of lysosome biogenesis, and the expression of a downstream osteoporosis-associated transmembrane protein 1 (OSTM1), a vital molecule involved in lysosome acidification in primary microglial cells. Aβ1-42 but not Aβ42-1 resulted in a significant release of tumor necrosis factor-α in primary microglia, but the total cellular TFEB was not changed. Further, Aβ induced a dose-dependent reduction of the TFEB in the nucleus of primary microglial cells, coincident with the increase in the plasma, as revealed by Western blot and confocal microscopy. In addition, a dramatic decrease of OSTM1 expression was observed in the Aβ-challenged microglial cells, along with the intracellular pH steady state, indicating the inadequate lysosomal acidification. These data suggest that Aβ might result in a lysosomal dysfunction via inhibiting nuclear TFEB translocation in microglial cells.