ABSTRACT
A 30-d course of oral administration of a semipurified extract of the root of Withania somnifera consisting predominantly of withanolides and withanosides reversed behavioral deficits, plaque pathology, accumulation of ß-amyloid peptides (Aß) and oligomers in the brains of middle-aged and old APP/PS1 Alzheimer's disease transgenic mice. It was similarly effective in reversing behavioral deficits and plaque load in APPSwInd mice (line J20). The temporal sequence involved an increase in plasma Aß and a decrease in brain Aß monomer after 7 d, indicating increased transport of Aß from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Aß-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain Aß levels. However, significant increase in liver LRP and NEP occurred much earlier, at 7 d, and were accompanied by a rise in plasma sLRP, a peripheral sink for brain Aß. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain Aß, indicating that increase in liver LRP and sLRP occurring independent of Aß concentration could result in clearance of Aß. Selective down-regulation of liver LRP, but not NEP, abrogated the therapeutic effects of the extract. The remarkable therapeutic effect of W. somnifera mediated through up-regulation of liver LRP indicates that targeting the periphery offers a unique mechanism for Aß clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models.
