Disorders of the Nervous System
Author: Gabriel Cataldi | Email: gcataldi@immf.uncor.edu
Gabriel Cataldi1°, Mauricio Martin1°
1° Laboratory of Cellular and Molecular Neurobiology, INIMEC CONICET, Universidad Nacional de Córdoba
Cholesterol 24-hydroxylase (CYP46) catalyzes the hydroxylation of cholesterol to 24(S)-hydroxycholesterol [24(S)HOC], the main mechanism of cholesterol elimination from the brain. While CYP46 is primarily expressed in neurons, its expression increases in astrocytes under pathological conditions like traumatic brain injury or Alzheimer’s disease. We found that CYP46 levels are significantly elevated in reactive astrocytes treated with lipopolysaccharide (LPS) or proinflammatory cytokines (IL-6, IL-1β, TNFα). Additionally, CYP46 transcription is induced by H₂O₂, suggesting that reactive oxygen species (ROS) generated by LPS drive CYP46 expression. Supporting this, NAC, a potent antioxidant, prevents LPS-induced CYP46 expression.
Furthermore, IL-6 enhances amyloid precursor protein (APP) synthesis in rat astrocytes, and this effect is CYP46-dependent, as inhibiting CYP46 reduces IL-6-induced APP production. 24(S)HOC-treated astrocytes show increased APP levels, with transcriptional origins. 24(S)HOC also enhances APP processing, leading to APP-CTF fragments, potential precursors of amyloid beta.
Finally, LPS-treated reactive astrocytes accumulate cholesterol, likely increasing 24(S)HOC production. This suggests that under proinflammatory conditions, astrocytes may elevate APP synthesis and processing through a mechanism involving both CYP46 and increased cholesterol metabolism, potentially predisposing to Alzheimer’s disease.