2. Academic Validation
  3. 7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in Alzheimer's disease

7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in Alzheimer's disease

  • bioRxiv. 2025 Jan 28:2025.01.19.633810. doi: 10.1101/2025.01.19.633810.
Kayalvizhi Radhakrishnan 1 2 3,  Yiyu Zhang 4 5,  Oluwaseun Mustapha 4 5,  Thaddeus K Weigel 1 2,  Clint M Upchurch 6,  Xiaodong Tian 4 5,  Franklin Herbert 4 5,  Wenyuan Huang 4 5,  Norbert Leitinger 6,  Ukpong B Eyo 1 2,  Huiwang Ai 4 5,  Heather A Ferris 1 2 3
Affiliations

Affiliations

  • 1 Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, USA.
  • 2 Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
  • 3 Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA.
  • 4 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
  • 5 Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA.
  • 6 Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.
PMID: 39868327 DOI: 10.1101/2025.01.19.633810
Abstract

Oxidative stress is a prominent feature of Alzheimer's disease. Within this context, Cholesterol undergoes oxidation, producing the pro-inflammatory product 7-ketocholesterol (7-KC). In this study, we observe elevated levels of 7-KC in the brains of the 3xTg mouse model of AD. To further understand the contribution of 7-KC on the oxidative environment, we developed a method to express a genetically encoded fluorescent hydrogen peroxide (H2O2) sensor in astrocytes, the primary source of Cholesterol in the brain. With this sensor, we discovered that 7-KC increases H2O2 levels in astrocytes in vivo, but not when directly applied to astrocytes in vitro. Interestingly, when 7-KC was applied to a microglia cell line alone or mixed astrocyte and microglia cultures, it resulted in microglia activation and increased oxidative stress in astrocytes. Depletion of microglia from 3xTg mice resulted in reduced 7-KC in the brains of these mice. Taken together, these findings suggest that 7-KC, acting through microglia, contributes to increased astrocyte oxidative stress in AD. This study sheds light on the complex interplay between Cholesterol oxidation, microglia activation, and astrocyte oxidative stress in the pathogenesis of AD.

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