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...