Novel Therapeutic Targets for Alzheimer s Disease

Abstract

Alzheimer s disease (AD) is a progressive neurodegenerative disorder characterized by impaired memory and other cognitive deficits. Even though the genes associated with familial AD were discovered more than three decades ago, no cure has been developed yet. The drugs that are prescribed for AD currently provide only symptomatic relief and do not cure or alter the progression of the disease. Hence, the need for better therapeutic strategies is greater than ever The study and the thesis titled Novel therapeutic targets for Alzheimer s disease is divided into two parts: Part 1 titled Lipoprotein receptor related protein 1 as a therapeutic target for Alzheimer s disease and Part 2 titled Differential gene expression in entorhinal cortex of one-month old APPSwe/PS1dE9 animals . The scope of both the studies is described below. One of the lesser studied mechanisms of Aand#946; clearance from brain is the clearance via periphery. It is known that lowering the amyloid beta levels in blood or periphery leads to increased clearance of amyloid beta from the brain (Zlokovic et al, 2000; Zlokovic et al, 2008). We demonstrated in our laboratory that a partially purified extract of root of Withania somnifera completely reverses plaque pathology and behavioural deficits in APPSwe/PS1dE9 animals via upregulation of hepatic lipoprotein receptor related protein 1 (LRP) (Sehgal et al, 2012). The soluble form of LRP (sLRP) circulates in blood and binds and clears Aand#946;42 from blood. Upregulation of hepatic LRP leads to increased levels of sLRP in blood and hence, increased clearance of Aand#946;42 from blood. This in turn results in increased efflux of Aand#946;42 monomers from brain into periphery which leads to breakdown of plaques in the brain. Inhibition of hepatic LRP completely diminished this therapeutic effect. Identification of the active principle(s) in the semi-purified extract of root of Withania somnifera will help in designing a novel class of therapeutics that target Aand#946; clearance from brain through periphery. Therefore, the objective...