Objectif
The pathogenic event common to all forms of Alzheimer’s disease (AD) is the abnormal accumulation of the amyloid β-peptide (Aβ) in specific regions of the brain. This accumulation of Aβ is considered a key pathological event in AD and is the basis of the so-called amyloid hypothesis of the disease. Therefore, therapeutic approaches that reduce the accumulation of Aβ are currently being sought. It has been shown definitively that the generation and clearance of Aβ in the brain is regulated by cholesterol levels. Compounds that perturb free cholesterol such as acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors have been shown both in vitro and in vivo to reduce Aβ production and secretion. However, it is generally the case that ACAT inhibitors exhibit poor oral activity. The beauveriolides are a new class of fungal metabolites that have been shown to be orally active ACAT inhibitors and are currently being investigated as potential therapeutics for atherosclerosis. NB No studies have been reported to date on the investigation of the Aβ-inhibitory effect of the natural product beauveriolides or beauveriolide-inspired compounds. Therefore, the hypothesis being tested in this proposal is that natural product beauveriolides or beauveriolide-inspired libraries of compounds should reduce Aβ-production and secretion in vitro via inhibition of ACAT and hence perturbation of cholesterol homeostasis. They would in such a case be a NEW CLASS of potential AD therapeutics working via an established mechanism of action and hence this proposal.
Champ scientifique
Thème(s)
Appel à propositions
FP7-PEOPLE-2009-IEF
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Régime de financement
MC-IEF - Intra-European Fellowships (IEF)Coordinateur
OX1 2JD Oxford
Royaume-Uni