014 | Cholesterol hydroxylation in astrocytes under an inflammatory context: A Susceptibility Factor for Alzheimer’s Disease?

Cellular and Molecular Neurobiology

Author: Gabriel Cataldi | Email: gcataldi@immf.uncor.edu

Gabriel Cataldi , Mauricio Martin

1° Laboratorio de Neurobiologia, Instituto de Investigación Médica Mercedes y Martín Ferreyra – INIMEC-CONICET-UNC

Cholesterol 24-hydroxylase (CYP46) catalyzes cholesterol hydroxylation to 24(S)HOC, crucial for brain cholesterol elimination. While CYP46 is mainly associated with neurons, brain damage like traumatic brain injury or Alzheimer’s escalates its expression in astrocytes. Yet, CYP46’s role in astrocytes during pathologies remains uncertain.
Our findings reveal elevated CYP46 levels in reactive astrocytes exposed to lipopolysaccharide (LPS) or IL-6, a proinflammatory cytokine. Furthermore, IL-6 induces APP synthesis in rat primary reactive astrocytes via CYP46 mediation; blocking CYP46 impairs this IL-6-induced process. Our results establish a connection between CYP46 and APP, indicating heightened APP levels in 24(S)HOC-treated reactive cortical astrocytes compared to controls. Notably, this increase in APP protein arises transcriptionally, as Actinomycin D treatment fails to elevate APP mRNA levels. Our initial data suggests that 24(S)HOC may operate through histone 3 remodeling and acetylation-associated epigenetic mechanisms.
Considering A?’s antimicrobial potential, we propose that under brain proinflammatory states, prompted by microbial infections, 24(S)HOC might mediate APP production and processing in astrocytes as a defense. Conversely, this process could predispose individuals to Alzheimer’s disease. To explore this, we’ve established an in vivo brain infection model utilizing C. albicans.