7-ketocholesterol Contributes to Microglia-driven Increases in Astrocyte Reactive Oxygen Species in Alzheimer's Disease

Overview

Journal bioRxiv

Date 2025 Jan 27

PMID 39868327

Authors

Kayalvizhi Radhakrishnan

Yiyu Zhang

Oluwaseun Mustapha

Thaddeus K Weigel

Clint Upchurch

Clint M Upchurch

Xiaodong Tian

Franklin Herbert

Wenyuan Huang

Norbert Leitinger

Ukpong B Eyo

Ukpong Bassey Eyo

Huiwang Ai

Heather A Ferris

Affiliations

Soon will be listed here.

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 (HO) sensor in astrocytes, the primary source of cholesterol in the brain. With this sensor, we discovered that 7-KC increases HO 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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