High Resolution Structure of Abeta Peptide Oligomers by NMR
Jaime López de la Osa, Marta Bruix, Douglas Laurents
Douglas Laurents

Abeta is the main protein component of amyloid plaques, a hallmark of Alzheimer's disease. These molecules are produced one by one in the nerve cell membrane, but then associate together to form small, soluble clusters called "oligomers". Over time, these soluble oligomers slowly bind together to form large, insoluble amyloid fibers and plaques. Recent experiments have provided evidence that soluble oligomers of Abeta, and not the amyloid fibers or plaques are responsible for the loss of nerve cell function and death occurring in early Alzheimer's disease. For example, even tiny amounts of these oligomers inhibit the nerve signals associated with new memories and kill nerve cells. Despite the importance of Abeta soluble oligomers, their structure remains unknown. We are experienced in using the experimental method called "Nuclear Magnetic Resonance" or "NMR" for short, which is probably the best technique for determining the structure of molecules like Abeta soluble oligomers at high resolution.

We have recently studied isolated Abeta soluble molecules and found two regions which have an extended conformation and are likely to play important roles in oligomer formation. We also proposed a plausible, low resolution structure for the soluble, neurotoxic oligomers. (J. Biol. Chem. In Press).

Over the next two years, we will determine the high resolution structure of the soluble neurotoxic Abeta oligomers using the latest and most powerful NMR instruments and experiments. We will work with the laboratory directed by Prof. A. Chakrabartty, which has experience in making Abeta by chemical methods and in studying the formation of its oligomers. We will determine the conformation of two soluble neurotoxic oligomers: a large, ball-shape oligomer present in dilute acid solution, and a small oligomer that forms in the brain and in test tubes under physiological conditions. Research work from other laboratories has shown that Abeta molecules can interact strongly with zinc ions or copper ions. Abeta molecules also bind strongly to particular lipids called "gangliosides" which are abundant in the nerve cell membrane near the synapses and in membrane regions rich in cholesterol. We will characterize the conformational changes that the Abeta molecules undergo in the presence of metal ions and determine the high resolution structure of Abeta bound to ganglioside molecules, alone or within lipid vesicles which mimic the nerve cell membrane. We expect these experiments to reveal new, important knowledge for understanding the biological origin of Alzheimer's disease and for designing new treatment strategies.