The appearance of amyloid deposits in the brain is the diagnostic biochemical hallmark of Alzheimer's disease. Substantial evidence has accumulated that suggests that amyloid formation leads to neurodegeneration. Since amyloid formation occurs slowly in healthy individuals, it may be the case that it is the rate of formation of amyloid that is the key determinant as to whether an individual will be afflicted. Therefore, the inhibition, or deceleration, of amyloid formation may be a viable therapeutic strategy against Alzheimer's disease. In order to design potential drugs, it is critical to understand the structure of the amyloid deposits and the mechanism of their formation. This proposal focusses on those two issues. Dr. Lansbury has devised a new approach, based on solid-state NMR and Fourier-transform infrared spectroscopy, to determine the three-dimensional structure of amyloid. It is proposed to now apply this methodology for the determination of AD amyloid. Dr. Lansbury has determined that amyloid formation, like a crystallization, follows a nucleation-dependent kinetic pathway. This proposal details efforts to elucidate the details of the kinetic pathway. Dr. Lansbury has shown that apoliprotein E, which has been implicated in AD by genetic studies, inhibits amyloid formation by slowing down the nucleation step. This proposal discusses efforts to determine the precise mode of action of apoE and to relate its structure/conformation to this function. Dr. Lansbury has recently determined that the neuronal peptide NAC is capable of accelerating amyloid formation by a seeding mechanism. Finally, it is hoped that the research will lead to the design of molecules that act as inhibitors of amyloid formation. The structure of these molecules will derive from the ongoing studies of amyloid structure.
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