27-Hydroxycholesterol triggers microglial senescence subsequent to iron over-loading contributes to brain aging,...

Area of Science:

• Neuroscience
• Gerontology
• Biochemistry

Background:

• Brain aging is a significant contributor to cognitive decline and Alzheimer's disease (AD).
• Microglial senescence, driven by aging, exacerbates neuroinflammation and brain aging.
• Mechanisms driving microglial aging are not fully understood.

Purpose of the Study:

• To investigate the role of 27-hydroxycholesterol (27-OHC) in promoting microglial senescence, iron overload, and neuroinflammation.
• To explore the association between 27-OHC levels and cognitive function in Alzheimer's patients.
• To identify the 27-OHC-iron axis as a potential therapeutic target.

Main Methods:

• Clinical analysis of plasma 27-OHC levels and Mini-Mental State Examination (MMSE) scores in AD patients.
• Administration of 27-OHC to mice to assess cognitive and behavioral changes, and measure senescence markers.
• In vitro studies using BV-2 cells to examine 27-OHC effects on iron homeostasis, oxidative stress, and mitochondrial function.
• Treatment with deferoxamine (DFX) to evaluate its impact on microglial senescence and ferroptosis.

Main Results:

• A negative correlation was found between plasma 27-OHC levels and MMSE scores in AD patients.
• 27-OHC administration induced cognitive impairment, anxiety, senescence markers, and M1 microglial polarization in mice.
• In vitro, 27-OHC disrupted iron homeostasis, increased reactive oxygen species (ROS), and impaired mitochondrial function in microglial cells.
• Deferoxamine (DFX) treatment reduced microglial senescence and ferroptosis.

Conclusions:

• 27-hydroxycholesterol (27-OHC) accelerates brain aging by inducing microglial senescence and iron overload.
• The 27-OHC-iron axis represents a novel therapeutic target for cholesterol-driven neurodegeneration.
• Targeting microglial senescence and iron dysregulation may offer a strategy to combat cognitive decline in AD.