Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No. 8 • December 2012

About 60 years ago, I said to my father, “Old Mr. Senex is showing his age; he sometimes talks quite stupidly.” My father replied, “That isn’t age. He’s always been stupid. He is just losing his ability to conceal it.”
— Robertson Davies,
“You’re Not Getting Older, You’re Getting Nosier,”
in the New York Times Book Review

Ashwagandha Reverses Alzheimer’s Pathology in a Mouse Model By Upregulating Liver Protein

A new paper1 reports on a “remarkable therapeutic effect” (words of the authors) of W. somnifera (Withania somnifera, also known as Ashwagandha) that the researchers found to clear amyloid beta from the brain as well as reversing the behavioral deficits and pathology seen in a mouse Alzheimer’s disease model via the upregulation of LRP in the liver. LRP is “the major cell surface receptor for clearance of Abeta from brain interstitial fluid across the blood-brain barrier … [i]t is also involved in the endocytosis of APP [importing into cells of APP] and thereby influences Abeta production within neurons.”1

As the authors explain, “influx and efflux of brain Abeta are regulated by receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein LRP [also called LDLR], respectively. The soluble form of LRP in plasma (sLRP) is a peripheral sink for Abeta that aids its sequestration. In AD [Alzheimer’s disease], plasma sLRP and LRP1 at the blood brain barrier are reduced, whereas RAGE expression is increased, resulting in accumulation of brain Abeta.” In their paper,1 the researchers found that “a WS [W. somnifera] extract reverses behavioral deficits and plaque pathology and reduces the Abeta burden in middle-aged and old APP/PS1 mice through upregulation of liver LRP, leading to increased clearance of Abeta. The therapeutic effects of WS were reproducible in APPSwInd J20 mice, another model of AD, in which behavioral deficits were reversed and plaque load decreased significantly.” “Indeed, the ability of WS to induce liver LRP may be extremely important, given that cell surface LRP in liver is required for the rapid systemic clearance of the toxic Abeta peptide and subsequent degradation of this peptide by proteases in the liver.”1

The authors note that a rather high dose of the withanolides and withanosides (major constituents of the WS extract) was used in this study.

Withanoside A and withanoside IV (which are, as noted above, major constituents of the roots of WS) have been reported in another study (cited in paper #1) to help promote neurite outgrowth in cultured neurons and in rodents injected with Abeta25–35. In a different paper,2 WS root extract administered orally (at either 25 mg/kg or 50 mg/kg) significantly decreased the changes induced in adult Wistar rats (hyperglycemia, glucose intolerance, increase in plasma corticosterone levels, cognitive deficits, immunosuppression, mental depression, and others) by chronic stress (mild unpredictable footshock). The treatments (the two doses of WS extract or 100 mg/kg Panax ginseng) were compared to each other and to placebo and were administered 1 hour before footshock for 21 days.

Most of the effects of chronic stress were inhibited similarly by both doses of WS and by Panax ginseng at 100 mg/kg. Although WS at 50 mg/kg. was reported to have memory enhancing activity per se, PG did not, but both herbs could inhibit the adverse effects of chronic stress on the test for retention of learned tasks. In summing up, the authors state: “An overall activity indicated of WS anti-CS [chronic stress] effect of WS and PG showed that WS (25 and 50 mg/kg p.o.) was approximately equi-effective as PG (100 mg/kg p.o.) whereas WS (50 mg/kg p.o.) exhibited a higher antistress activity.”


  1. Sehgaj et al. Withania somnifera reverses Alzheimer’s disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci USA 109(9):3510-5 (2012).
  2. Bhattacharya and Muruganandam. Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress. Pharmacol Biochem Behav 75:547-55 (2003).

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