The role of CYP46 at inflammatory context: 24(S)hydroxycholesterol as predisposing agent for Alzheimer’s disease

CATALDI, GABRIEL G.; MAURICIO G MARTÍN

Congreso; Reunión SAIB 2022; 2022

CYP46 carries out the hydroxylation of cholesterol to 24(S)HOC, which is the main mechanismof cholesterol elimination from the brain. CYP46 has been mainly reported in neuronalpopulations, however, in cases of brain damage such as traumatic brain injury or Alzheimer’sdisease CYP46 increases its expression in astrocytes. However, the role that CYP46 would playin astrocytes in pathological conditions is unknown.We found that CYP46 levels are greatly increased in reactive astrocytes treated withlipopolysaccharide (LPS) and IL-6. Accordingly, IL-6 was able to increase APP synthesis inprimary astrocytes. Providing a link between CYP46 and APP, our results show that 24(S)HOC-treated primary cortical astrocytes showed a marked increase in APP levels compared tocontrol cells. In addition, when we inhibit the activity of CYP46 with Voriconazole in aninflammatory context induced by IL-6, astrocytes lose the ability to produce APP, compared tocontrol cultures Our data indicate that 24(S)HOC appears to exert its role through epigeneticmechanisms. Also, we observed that this oxysterol acts differentially in the different cell types.In astrocytic cultures, 24(S)-HOC downregulates the H3k9Ac epigenetic mark, whereas incortical neurons it upregulates it.We propose that under a proinflammatrory context, as for example a microbial infection in thebrain, 24(S)HOC would mediate the production of APP and Abeta in astrocytes to face theaggression but on the other side it would predispose to Alzheimer's disease.