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Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Amyloid β-Induced Redistribution of Transcriptional Factor EB and Lysosomal Dysfunction in Primary Microglial Cells
Xingzhi Guo1, Peng Tang1, Li Chen1
1Department of Neurology, Shaanxi Provincial People's Hospital, and the Third Affiliated Hospital, Xi'an Jiaotong University School of MedicineXi'an, China.
Abstract:
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.
Insights
Amyloid beta (Aβ) impairs microglial function in Alzheimer's disease by inhibiting nuclear TFEB translocation, leading to lysosomal dysfunction and reduced Aβ clearance. This study reveals a novel mechanism of microglial impairment.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Impaired amyloid-beta (Aβ) clearance by microglia is linked to Alzheimer's disease pathology.
- Microglial dysfunction, particularly lysosomal impairment, may hinder Aβ degradation.
- The precise mechanisms of Aβ-induced microglial impairment are not fully understood.
Purpose of the Study:
- To investigate the effects of Aβ on microglial lysosomal function.
- To examine the impact of Aβ on the nuclear translocation of transcription factor EB (TFEB).
- To assess the expression of osteoporosis-associated transmembrane protein 1 (OSTM1) in Aβ-treated microglia.
Main Methods:
- Primary microglial cells were treated with Aβ peptides (Aβ1-42 and Aβ42-1).
- Western blot and confocal microscopy were used to analyze TFEB localization and OSTM1 expression.
- Tumor necrosis factor-alpha release and intracellular pH were measured.
Main Results:
- Aβ1-42, but not Aβ42-1, induced significant TNF-α release.
- Aβ reduced nuclear TFEB levels in a dose-dependent manner, with increased TFEB in the plasma.
- OSTM1 expression decreased, and lysosomal acidification was impaired in Aβ-treated microglia.
Conclusions:
- Aβ peptides impair microglial function by inhibiting TFEB nuclear translocation.
- This inhibition leads to lysosomal dysfunction, characterized by reduced OSTM1 expression and impaired acidification.
- These findings suggest a novel mechanism contributing to Alzheimer's disease pathogenesis via microglial impairment.
