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

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 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.herbal extract | dementia | neurodegenerative disease A lzheimer's disease (AD) is characterized by progressive dysfunction of memory and higher cognitive functions. Pathological hallmarks include senile plaques, neurofibrillary tangles, dystrophic neurites, gliosis, and neuroinflammation. Cholinesterase inhibitors and the NMDA antagonist memantine, the commonly used drugs for AD, provide symptomatic relief but do not alter the course of disease. No curative treatment is available, and research focuses on drugs for slowing disease progression or providing prophylaxis.The majority of AD cases are sporadic in nature. The small fraction of familial cases are caused primarily by mutations in three genes: amyloid precursor protein (APP), presenilin1 (PS1), and presenilin 2 (PS2). These mutations result in abnormal processing of APP and increased generation of β amyloid peptide 1-42 (Aβ42), which aggregates as β sheets (1). Treatment strategies have focused on reducing β-amyloid load through (i) inhibition of γ-or β-secretases or activation of α-secretase; (ii) inhibition of Aβ aggregation; (iii) activation of proteases, such as neprilysin (NEP); and (iv) active and passive immunotherapy (2, 3).Among other mechanisms, influx and efflux of brain Aβ are regulated by receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein (LRP), respectively (4). The soluble form of LRP in plasma (sLRP) is a peripheral sink for Aβ that aids i...

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

“…Whether liver dysfunction also increases the Aβ load in the brain remains unknown; however, treatments that enhance LRP1-mediated Aβ uptake by the liver alleviate both the burden of Aβ in the brain and cognitive impairment 74,109 . These observations suggest that improving the Aβ clearance capacity of the liver is a potential systemic therapeutic approach for AD.…”

Cold stress affects antioxidative response and accumulation of medicinally important withanolides in Withania somnifera (L.) Dunal

“…It has received considerable attention throughout the world due to its potential preventive and curative role in several clinical problems including neurodegeneration, in the treatment of tumours and in its use as an antihelminthic (Sangwan et al, 2004;Tuli et al, 2009;Yang et al, 2011;Sehgal et al, 2012). The medicinal properties of W. somnifera have been attributed to withanolides synthesized in the leaves and roots.…”

A truncated and dimeric format of an Affibody library on bacteria enables FACS‐mediated isolation of amyloid‐beta aggregation inhibitors with subnanomolar affinity

“…One strategy to prevent aggregation of amyloid complexes could potentially be by shifting free Ab levels from the brain to the periphery, according to the peripheral sink mechanism. In order to attain this shift, it would be critical to use binding agents with high affinity, as levels of Ab peptides in the blood are low [10,46,48]. To meet these ends, we here set out to generate improved highaffinity variants of the previously generated Ab-specific Affibody molecule.…”