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

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

SUBMITTER: Guo X 

PROVIDER: S-EPMC5515861 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature