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Center for Nonlinear Studies |
Alzheimer’s disease (AD) is a disease of aging, and as medical advances against other diseases enable people to live longer, the incidence of AD is expected to increase dramatically. AD affects nearly 10% of people over the age of 65, and the first baby boomers reached 65 this year. Although AD is clearly one of the key health issues of our time, our understanding of its molecular causes remains limited. Several pharmaceuticals are prescribed for AD; however, these drugs merely treat the symptoms. Currently, no available therapeutics target the underlying causes of this debilitating neurodegenerative disease. At the molecular level, AD is disease of protein misfolding. Numerous genetic and biochemical studies indicate that misfolding and aggregation of the Alzheimer’s (A-beta) peptide causes a multi-step cascade that leads to inflammation, synaptic changes, neurotransmitter loss, and ultimately, to cognitive decline and death. Our research focuses on two central questions in this field. First, we seek to determine the molecular determinants of A-beta aggregation: Why does the A-beta sequence have such a high propensity to aggregate? Which mutations might prevent aggregation? Second, we are searching for inhibitors of A-beta aggregation. Toward this goal, we developed a novel high throughput method that enables screening of vast libraries of compounds for specific inhibitors of A-beta aggregation. Our screen is based on technology originally developed by Geoff Waldo at LANL. Implementation of this screen on a library of > 65,000 compounds enabled the isolation of several compounds that inhibit A-beta aggregation. Recently, we tested these compounds in an animal model of Alzheimer’s disease and found that they diminish cognitive decline and enhance life expectancy.
Host: Giovanni Bellesia, T-6 and CNLS