AIBP controls TLR4 inflammarafts and mitochondrial dysfunction in a mouse model of Alzheimer’s disease

Abstract

Microglia-driven neuroinflammation plays an important role in the development of Alzheimer’s disease (AD). Microglia activation is accompanied by the formation and chronic maintenance of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 and other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft-expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aβ) induced TLR4 inflammarafts in microglia in vitro and in APP/PS1 mice. Mitochondria inApoa1bp-/-APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased ROS and dilated ER. Aβ plaques and neuronal cell death were significantly increased, and survival decreased inApoa1bp-/-APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in AD associated oxidative stress and neurodegeneration.