| First Author | Sehgal N | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 9 | Pages | 3510-5 |
| PubMed ID | 22308347 | Mgi Jnum | J:182629 |
| Mgi Id | MGI:5316187 | Doi | 10.1073/pnas.1112209109 |
| Citation | Sehgal N, et al. (2012) Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci U S A 109(9):3510-5 |
| abstractText | 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 beta-amyloid peptides (Abeta) 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 Abeta and a decrease in brain Abeta monomer after 7 d, indicating increased transport of Abeta from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Abeta-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain Abeta 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 Abeta. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain Abeta, indicating that increase in liver LRP and sLRP occurring independent of Abeta concentration could result in clearance of Abeta. 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 Abeta clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models. |
