27-Hydroxycholesterol triggers microglial senescence subsequent to iron over-loading contributes to brain aging, suppressed by Deferoxamine.
Abstract
Brain aging is a major factor in cognitive decline and Alzheimer's disease (AD) progression. Aging-induced microglial senescence critically drives inflammaging and brain aging processes. Nevertheless, the underlying reasons and mechanisms that promote microglial aging remain unclear. This study explores how 27-hydroxycholesterol (27-OHC), a key oxysterol, accelerates brain aging by promoting microglial senescence, iron overload, and neuroinflammation. Clinically, we observed a significant inverse correlation between plasma 27-OHC levels and Mini-Mental State Examination (MMSE) scores in AD patients, accompanied by reduced 24S-OHC concentrations. Experimental studies revealed that 27-OHC administration in mice induced hippocampal-dependent cognitive impairment and anxiety-like behaviors, concurrent with elevated expression of cellular senescence markers (P21, P16, SA-β-Gal) and M1 microglial polarization. In BV-2 cells, 27-OHC disrupted iron homeostasis (DMT1/ferritin/GPX4 dysregulation), elevating ROS and impairing mitochondrial function. Deferoxamine (DFX) mitigated microglial senescence and ferroptosis. These findings establish the 27-OHC-iron axis as a novel therapeutic target for combating cholesterol-driven neurodegeneration.
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Research summary
The paper claims that 27-hydroxycholesterol promotes microglial senescence and neuroinflammation, contributing to brain aging and cognitive decline. This research addresses mechanisms underlying microglial aging and neurodegeneration, which are critical for understanding and potentially mitigating age-related cognitive decline.
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