Faculty News
"Functional Screening of Small Molecules for Inhibiting the Ion Channel Activity of Beta-Amyloid Peptides"
Michael Mayer, PhD and R. Scott Turner, MD, PhD
2008 funding: $150,000; funding to date: $367,000
Alzheimer's disease (AD), the most common neurodegenerative disorder in the elderly, affects 4.5 million people in the US and 25 million people worldwide. AD is the fourth leading cause of death in industrialized societies and the third most expensive disease in the US. Current treatments provide only temporary and symptomatic benefits as AD invariably leads to progressive dementia, disability, and death. BME faculty member, Michael Mayer and Neurology clinician, Scott Turner are working together on an innovative approach to treating AD by focusing on a protein found in plaques in the brain, one of the hallmark characteristics of AD. It appears that these proteins "short circuit" neurons, disrupting normal brain activity. The project, now in its third year of funding from the Coulter Foundation, focuses on screening for molecules that can block the short circuit process.
It is the accumulation of amyloid plaques in the brain that is thought to distinguish AD from other neurodegenerative disorders. The major component of the amyloid plaques is a peptide, referred to as β-amyloid (Aβ) peptide, which aggregates into insoluble fibrillar structures. The Aβ peptide is a fragment of a transmembrane protein called amyloid precursor protein (APP), and the extracellular release of this peptide requires cleavage of APP by β- and ϒ-secretases in the membrane. Although the formation and removal of Aβ peptides are normal neurophysiological processes, accumulation of Aβ peptides in brain leads to deposition of Aβ plaques.
The team has already synthesized derivatives of nicotine and dopamine and showed that several of these patentable molecules bind strongly to Aβ fibrils. They have established cellular and toxicity assays with a human neuronal cell line and demonstrated that their optimized Aβ oligomer preparation is toxic. First results indicate that nicotine, bromonicotine, dopamine, morin, catechin, and tannic acid are able to reduce this Aβ toxicity. With the exception of tannic acid, these molecules are drug-like and were not toxic by themselves. Moreover, they established a functional assay to record ion channel activity of Aβ oligomers and showed that nicotine, dopamine, L-dopa, norepinephrine, tannic acid, and Congo red can inhibit the ion channel formation of Aβ peptides in planar lipid bilayers under certain conditions.
The research they have proposed for their third year of funding will be to continue to employ functional assays to investigate whether small molecules can effectively inhibit the neurotoxic ion channel activity of Aβ peptides in human neuronal cells and in reconstituted membrane bilayers. It will determine values for these molecules and it will test the toxicity and permeability through the blood brain barrier (BBB) of all promising molecules. The identified therapeutically-tolerable compounds with these characteristics will then be tested in primary neurons, and/or in behavioral studies with a mouse model of AD.
A list of all the U-M Coulter funded projects is found on the UM BME Coulter Site.
Posted on September 30, 2008, 10:34 am