| Autor: |
Shibuya, Yohei, Chang, Catherine C. Y., Li-Hao Huang, Bryleva, Elena Y., Ta-Yuan Chang |
| Předmět: |
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| Zdroj: |
Journal of Neuroscience; 10/22/2014, Vol. 34 Issue 43, p14484-14501, 18p |
| Abstrakt: |
Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) is a resident endoplasmic reticulum enzyme that prevents the buildup of cholesterol in membranes by converting it to cholesterol esters. Blocking ACAT1 pharmacologically or by Acatl gene knock-out (KO) decreases amyloidopathy in mouse models for Alzheimer's disease. However, the beneficial actions of ACAT1 blockage to treat Alzheimer's disease remained not well understood. Microglia play essential roles in the proteolytic clearance of amyloid β (Aβ) peptides. Here we show that Acatl gene KO in mouse increases phagocytic uptake of oligomeric Aβl-42 and stimulates lysosomal Aβl-42 degradation in cultured microglia and in vivo. Additional results show that Acatl gene KO or a specific ACAT1 inhibitor K604 stimulates autophagosome formation and transcription factor EB-mediated lysosomal proteolysis. Surprisingly, the effect of ACAT1 blockage does not alter mTOR signaling or endoplasmic reticulum stress response but can be modulated by agents that disrupt cholesterol biosynthesis. To our knowledge, our current study provides the first example that a small molecule (K604) can promote autophagy in an mTOR-independent manner to activate the coordinated lysosomal expression and regulation network. Autophagy is needed to degrade misfolded proteins/ peptides. Our results implicate that blocking ACAT1 may provide a new way to benefit multiple neurodegenerative diseases. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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