Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver.
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 β-amyloid peptides (Aβ) 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 Aβ and a decrease in brain Aβ monomer after 7 d, indicating increased transport of Aβ from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Aβ-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain Aβ 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 Aβ. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain Aβ, indicating that increase in liver LRP and sLRP occurring independent of Aβ concentration could result in clearance of Aβ. 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 Aβ clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models.
Division of Molecular and Cellular Neuroscience,  National Brain Research Centre, Nainwal Mode, Manesar, Haryana 122050,  India.
Neha
N
Sehgal
Alok
A
Gupta
Rupanagudi Khader
RK
Valli
Shanker Datt
SD
Joshi
Jessica T
JT
Mills
Edith
E
Hamel
Pankaj
P
Khanna
Subhash Chand
SC
Jain
Suman S
SS
Thakur
Vijayalakshmi
V
Ravindranath
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000097:blood*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D015260:Neprilysin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009928:Organ Specificity; D008517:Phytotherapy; D010936:Plant Extracts / Q000302:isolation & purification / Q000627:therapeutic use*; D018517:Plant Roots / Q000737:chemistry; D058225:Plaque, Amyloid / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D015854:Up-Regulation; D032341:Withania / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D016376:Oligonucleotides, Antisense; C508853:PSEN1 protein, human; D010936:Plant Extracts; D053764:Presenilin-1; D015260:Neprilysin