CYP46A1-APOE axis at the choroid plexus is compromised in Alzheimer's disease but is amenable to rescue.

Abstract

Removal of excess cholesterol from the brain in the form of 24-hydroxycholesterol (24-OH), produced by the CYP46A1 hydroxylase, is critical in diverse aspects of brain function, including clearance of toxic amyloid-β (Aβ). In the present study, we show that CYP46A1 is expressed by the choroid plexus (CP), where it decreases with Alzheimer's disease (AD) in both human patients and a transgenic mouse model of AD (5xFAD). We hypothesized, that CYP46A1 expression at the CP has a functional role, which may partake in disease modification. In addition, we have previously found that PD-1/PD-L1 immunotherapy improves cognition and reduces pathology in mouse models of neurodegeneration, and that the mechanism of action entails IFNγ-dependent mechanisms at the CP. Here, we investigated whether anti-PD-L1 treatment induces molecular pathways at the CP related to CYP46A1 activity as a regulator of cholesterol transport. We used an AAV viral vector for targeted CYP46A1 overexpression at the CP in order to examine the implications in AD pathology. We systemically injected 5XFAD mice with anti-PD-L1 and excised the CP for qPCR and ELISA in order to investigate potential molecular pathways at the CP related to cholesterol transport. We stimulated primary CP cultures with 24-OH and IFNγ and measured targets of interest via qPCR. Using a viral construct to target the CP, we demonstrate that CYP46A1 overexpression in 5xFAD mice ameliorates pathology. Furthermore, we show that systemic PD-L1 blockade in 5xFAD mice induces Cyp46a1 gene expression at the CP, followed by increased levels of apolipoprotein E (APOE), the main cholesterol carrier in the brain and a partaker in Aβ clearance. Using primary cultures of CP epithelium, we prove that 24-OH induces Apoe gene expression. Furthermore, we propose the transcription factor SP1 to mediate the IFNγ-dependent induction of Cyp46a1. Altogether, our findings suggest the CYP46A1-APOE axis at the CP as an amenable target to rescue AD.