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

Impaired clearance of Amyloid beta (A beta) 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 A beta, suggesting that microglial lysosome impairment may occur. However, the mechanism of A beta-induced impairment of microglia remains poorly understood. We observed the effects of A beta 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. A beta(1-42) but not A beta(42-1) resulted in a significant release of tumor necrosis factor-alpha in primary microglia, but the total cellular TFEB was not changed. Further, A beta 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 A beta-challenged microglial cells, along with the intracellular pH steady state, indicating the inadequate lysosomal acidification. These data suggest that A beta might result in a lysosomal dysfunction via inhibiting nuclear TFEB translocation in microglial cells.