Peripheral Clearance of β‑amyloid holds promise for the Treatment of Alzheimer’s Disease

Vidhi Khanna

Peripheral clearance  of amyloid beta
Peripheral clearance of amyloid beta  (Photo: Proc Natl Sci USA 2012 Feb 28; 109(9): 3199)

This piece was co-authored by Dhwani Rupani, Dhruvika Chawalla, Malhar Khakharia, Vidhi Khanna

Withania somnifera (Ashwagandha) extracts have been found to act peripherally to reduce b‑amyloidplaques in the brains of transgenic Alzheimer’s mice, presenting a new possibility in the treatment of Alzheimer’s disease. Alzheimer’s is characterised by increased concentrations of b‑amyloid in the brain, resulting from improper cleavage, increased expression, decreased degradation or altered homeostasis across blood brain barrier of the amyloid precursor protein (APP). b‑amyloid aggregation results in the formation of insoluble plaques which inhibit the functionality of neurons. Current treatment options target the activation of amyloid destroying enzymes, restoring proper cleavage mechanisms and immunotherapy. Receptors controlling the entry and exit of b‑amyloid between brain and periphery, peripheral destruction of b‑amyloid are viable and relatively untouched targets for the reversal of Alzheimer’s pathology. In this study researchers have successfully tapped these mechanisms by demonstrating that the increase in low density lipoprotein receptor related protein (LRP) in the liver of transgenic mice, eventually leads to improved b — amyloid clearance and cognitive functions.

In healthy people, products of the improperly cleaved peptide are cleared by membrane bound LRP, a low density protein found on brain capillaries. LRP isoform in the liver takes up the abnormally cleaved, toxic b‑amyloid leading to degradation by proteolytic enzymes. A subunit of this protein, soluble LRP (sLRP) binds to b‑amyloid in plasma, preventing its access to the brain. It has been proven that lower levels of LRP in the liver and sLRP in the plasma also contribute to Alzheimer’s disease pathology. Sehgal et al have reported increased levels of liver LRP and plasma sLRP following administration of Withania somnifera for 1 week to transgenic mice. This was followed by decrease in the brain β‑amyloid levels, increase in plasma b — amyloid levelsand eventually improved performance of the mice at behavioural tests. Additionally they reported increased expression of neprilysin, an enzyme that degrades b‑amyloid protein in the liver and decreased expression of the receptor for advanced glycation end products (RAGE), which is responsible for the influx of amyloid — b into the brain. The ability of the extract to act peripherally, without having to penetrate the blood brain barrier is a significant advantage over available drug therapies.

The study was conducted in two mice models, APP/PS1 and APPSwInd J20, both showing similar results. The scientists conclusively eliminated the possibility of the extract to influence improper cleavage mechanisms of the brain by simultaneously studying the expression of mRNAs for LRP concentrations and also for concentration of the cleavage enzymes. They then confirmed the improved brain pathology to be a primary result of increased liver LRP, independent of neprilysin concentrations. This extensive and very precise study deals with the effects of the extract on the brain, eliminating other plausible theories, providing exact time-frames and testing the results on two different models, giving due consideration to age and sex.

Yet, a few questions remain unanswered such as the active components of the extract, the possibility of LRP binding to other essential proteins in the body, its long term toxicity and most importantly its potential results in humans. It has also been reported that LRP at the blood brain barrier stimulates uptake of APP, which could worsen the condition of the patient. Furthermore, Withania somnifera eliminates only the β‑amyloid plaques in Alzheimer’s, leaving other pathological hallmarks like oxidative stress, change in the metal homeostasis, etc unhindered.

The blood brain barrier has consistently been a major dampener for the various drugs tested for Alzheimer’s due to its intricate restrictive mechanisms. This study is novel in that it deviates from conventional theories and provides agents that do not require penetration into the brain to be effective. If scientists are able to determine the active agents of the extract, a reduced, sophisticated dosage form may be designed.Efficient pharmacological reagents can also be developed that mimic the role of LRP in the brain. Withania somnifera, also known as Ashwagandha, is an important component of Ayurvedic medicine. Thus, the research done by Sehgal at al leaves open a wide stage for the use of Ayurveda in treating Alzheimer’s disease, possibly providing some hope to the millions of people suffering from this dreaded senile disease.

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