Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver

Sehgal, Neha and Gupta, Alok and Valli, Rupanagudi Khader and Joshi, Shanker Datt and Mills, Jessica T and Hamel, Edith and Khanna, Pankaj and Jain, Subhash Chand and Thakur, Suman S and Ravindranath, Vijayalakshmi (2012) Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. In: Prpceedings of the National Academy of Sciences of The United States of America, 109 (9). pp. 3510-3515.

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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 beta-amyloid peptides (A beta) 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 A beta and a decrease in brain A beta monomer after 7 d, indicating increased transport of A beta from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the A beta-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain A beta 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 A beta. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain A beta, indicating that increase in liver LRP and sLRP occurring independent of A beta concentration could result in clearance of A beta. 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 A beta clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models.

Item Type:	Journal Article
Publication:	Prpceedings of the National Academy of Sciences of The United States of America
Publisher:	National Academy of Sciences
Additional Information:	Copyright of this article belongs to National Academy of Sciences.
Keywords:	herbal extract;dementia;neurodegenerative disease
Department/Centre:	Division of Biological Sciences > Centre for Neuroscience Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	20 Mar 2012 11:31
Last Modified:	20 Mar 2012 11:31
URI:	http://eprints.iisc.ac.in/id/eprint/44015

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