Cholesterol 24-hydroxylase: Brain cholesterol metabolism and beyond

Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The major elimination pathway of brain cholesterol is its hydroxylation into 24 (S)-hydroxycholesterol by the cholesterol 24-hydroxylase (CYP46A1). Interestingly, there seems to be an association between CYP46A1 and high-order brain functions, in a sense that increased expression of this hydroxylase improves cognition, while a reduction leads to a poor cognitive performance. Moreover, increasing amount of epidemiological, biochemical and molecular evidence, suggests that CYP46A1 has a role in the pathogenesis or progression of neurodegenerative disorders, in which up-regulation of this enzyme is clearly beneficial. However, the mechanisms underlying these effects are poorly understood, which highlights the importance of studies that further explore the role of CYP46A1 in the central nervous system. In this review we summarize the major findings regarding CYP46A1, and highlight the several recently described pathways modulated by this enzyme from a physiological and pathological perspective, which might account for novel therapeutic strategies for neurodegenerative disorders.