Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver
Open accessAbstract
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.
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Root extract treatments led to low-density lipoprotein receptor-related protein upregulation, thereby boosting amyloid-beta clearance and ameliorating Alzheimer's disease pathology in APP/PS1 mice.
“Consequently, root extract treatments led to low-density lipoprotein receptor-related protein upregulation, thereby boosting Aβ clearance and ameliorating AD pathology in APP/PS1 mice [91].”
From The Multifaceted Role of Neuroprotective Plants in Alzheimer’s Disease Treatment (2022) · cites this paper as [91]
The two studies provide evidence for Withania somnifera's enhancing roles in memory and executive function in subjects with mild cognitive impairment.
“As such, these two studies provide evidence for W. somnifera’s enhancing roles in memory and executive function in subjects with MCI [91,94].”
From The Multifaceted Role of Neuroprotective Plants in Alzheimer’s Disease Treatment (2022) · cites this paper as [91]
The ameliorative effects of Withania somnifera semipurified extracts were mediated via enhancement of liver low-density lipoprotein receptor-related protein.
“These ameliorative effects were mediated via the enhancement of liver low-density lipoprotein receptor-related protein.”
From The Multifaceted Role of Neuroprotective Plants in Alzheimer’s Disease Treatment (2022) · cites this paper as [91]
Administering semipurified extracts of Withania somnifera orally inhibited amyloid-beta peptide accumulation and reversed behavioral impairment in APP/PS1 mice models of Alzheimer's disease.
“Similarly, administering semipurified extracts of W. somnifera orally inhibited Aβ peptide accumulation and reversed behavioral impairment in APP/PS1 mice models of AD [91].”
From The Multifaceted Role of Neuroprotective Plants in Alzheimer’s Disease Treatment (2022) · cites this paper as [91]
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References 19 · Cited by 390
- Authors
- Sehgal, N., Gupta, A., Valli, R. K., Joshi, S. D., Mills, J. T., Hamel, E., Khanna, P., Jain, S. C., Thakur, S. S., & Ravindranath, V.
- Affiliations
- National Brain Research Centre (IN)
- Montreal Neurological Institute and Hospital (CA)
- Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4;
- University of Delhi (IN)
- Molecular Biophysics Unit and
- Indian Institute of Science Bangalore (IN)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-01-30
- Volume
- 109
- Issue
- 9
- Pages
- 3510-3515
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3295277
- OpenAlex
- W2085872177
- Cited by
- 390
- References
- 19
- Citations by year
- 2026: 22 · 2025: 33 · 2024: 29 · 2023: 29 · 2022: 30 · 2021: 39 · 2020: 39 · 2019: 19 · 2018: 8 · 2017: 40 · 2016: 21 · 2015: 21 · 2014: 23 · 2013: 27 · 2012: 10
- FWCI
- 17.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- NOT FOUND REPOSITORY (Indian Institute of Science Bangalore) (acceptedVersion)
- Funders
- Canadian Institutes of Health Research (84275_1)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Complementary and alternative medicine › Phytochemicals and Medicinal Plants
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
- Keywords
- Withania somnifera, Alzheimer's disease, amyloid-beta clearance, low density lipoprotein receptor-related protein, neprilysin, withanolides, APP/PS1 mice, liver, cerebral microvasculature, behavioral deficits, amyloid plaques
- MeSH terms
- Administration, Oral, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Drug Evaluation, Preclinical, Liver, Male, Phytotherapy, Mice, Transgenic, Organ Specificity, Plant Extracts, Neprilysin, Up-Regulation, Amyloid beta-Peptides, Oligonucleotides, Antisense, Amyloid beta-Protein Precursor, Microglia, Plant Roots, Maze Learning, Low Density Lipoprotein Receptor-Related Protein-1, Withania, Mice, Presenilin-1, Plaque, Amyloid
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