Cholesterol 24-hydroxylase at the choroid plexus restrains local inflammation and protects overall brain function

Inflammation of the choroid plexus (CP), the interface between blood and cerebrospinal fluid, impacts the brain in aging and disease. Here, we report that the CP epithelium in mice and humans expresses CYP46A1 (cholesterol 24-hydroxylase), a brain-specific enzyme. CP CYP46A1 expression levels were found to be reduced in a mouse model of amyloidosis (5xFAD) and in aged mice, as well as in postmortem samples from COVID-19 victims. Bulk RNA-sequencing revealed that the CP epithelium responds in vitro to the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, by downregulating inflammatory transcriptomic signatures that we found in silico to be expressed in the CP across multiple neurological conditions. Moreover, the inflammatory cytokine TNF-a reduced CP Cyp46a1 expression, both in vitro and ex vivo, whereas Cyp46a1 overexpression attenuated the CP response to TNF-a. We propose that CYP46A1 plays a key regulatory role in CP homeostasis, with implications for various CNS pathologies, including sequelae of viral infections. Overall design: Transcriptional profiling of choroid plexus epithelium cell cultures treated with DMSO/24-OH.