Drug Discovery

Anti-tangle

Control of Microtubule Assembly in the Nervous System: Novel Approach for the Prevention of Neurodegenerative Diseases

Investigator(s): Etienne-Emile Baulieu, MD, PhD

Institution(s): MAPREG, Paris, France

Duration: 2002 - 2003

Summary:

Pregnenolone (PREG) is the most abundant neurosteroid in the human brain and has both neuroprotective and neurotophic activities. Dr. Baulieu and colleagues discovered that PREG’s neuroprotective activities are mediated by its stimulation of microtubule assembly and stability. The microtubular system is the major component of the neuronal skeleton and is required for the maintenance of normal neuronal physiological function. Major neuronal skeletal changes and microtubule destabilization are characteristic of several neurodegenerative diseases including Alzheimer’s disease (AD). Microtubule destabilization may play a direct role in the formation of neurofibrillary tangles (NFTs), the “tombstones” of dying neurons found in AD associated with dementia. Scientists at MAPREG have screened focused libraries of compounds for the purpose of discovering PREG-related lead compounds with improved microtubule assembly properties. In this program lead compounds will be evaluated for their pharmacokinetic and microtubule-stabilizing properties in a tangle forming transgenic mouse model of AD. If successful this program will lead to novel therapeutics that work by protecting the neuronal skeleton in the aging brain and neurodegenerative disorders such as AD. The direct results of the proposed experiments should lead to advancement of the PREG compounds to clinical trials for AD.