Pregnane X receptor activation regulate amyloid transport to improve cognition functions in Alzheimer's disease

To explore the concept about nuclear receptor pregnane X receptor (PXR) activation could be beneficial for the Alzheimer's disease (AD) treatment, as well as the underlying mechanism.

For in vitro experiments, human brain microvascular endothelial cells (hCMEC/D3) were exposed to Aβ₄₂ and hyperforin (HPF), a human PXR agonist followed by measurement of P-glycoprotein(P-gp)and low-density lipoprotein receptor-related protein 1 (LRP1) expression. Further, 7 months old 5 × FAD mice were used for in vivo experiments. Due to the species-difference characteristics of PXR, these mice were treated with pregnenolone carbonitrile (PCN, a rodent PXR agonist) rather than hPXR agonist, or corn oil for 28 days. Meanwhile, untreated C57BL/6 mice were used as the control group. The improvements of animal behavior were evaluated by Morris water maze and novel arm exploration test. The pathological profiles were assessed by immunohistochemistry and transmission electron microscopy. The cerebral blood flow (CBF) and Aβ transporters were analyzed by speckle contrast imaging and Western blot respectively.

In vitro experiments showed that the P-gp and LRP1 levels in hCMEC/D3 were reduced due to exposure of Aβ₄₂, while HPF can restore their expression levels. 5 × FAD mice treated with the PCN improved cognitive functions and cerebral blood flow. These functional improvements were associated with a reduction in amyloid plaques, cerebral amyloid angiopathy, neuroinflammation and a recovery of blood-brain barrier transport function. The underlying mechanisms could be that PXR activation up-regulates the expression of P-gp and LRP1 and inhibits inflammation via STAT3, and increases the clearance of Aβ42 in the brain.

These results demonstrate the beneficial impact of PXR activation on cognitive functions, parenchymal amyloid plagues and cerebral angiopathy, and highlights the therapeutic potential of PXR agonists for treatment of AD patients.