Alzheimer's disease is a devastating neurodegenerative disorder that afflicts over 5 million people in the US. One of the dominant pathological features of the disease is the deposition of beta-amyloid as fibrillar aggregates, in extracellular amyloid plaques. According to the widely held 'amyloid cascade' hypothesis, aggregation of beta-amyloid is causally linked to neuronal dysfunction and death. Beta-amyloid is a 4kDa peptide clipped from a precursor protein, APP. In an effort to develop an animal model of Alzheimer's disease, researchers have generated transgenic mice that express APP. The mice exhibit extensive beta-amyloid deposits, but surprisingly there is little neurotoxicity. Recently, it has been demonstrated that the transgenic mice upregulate expression of transthyretin (TTR), and the data strongly suggests that TTR protects the mouse neuron from beta-amyloid toxicity. These results raise several questions: how does TTR exert its protective effect? Is it lost in Alzheimer's patients? Can it be restored? In this presentation we will describe our efforts to answer these questions. We have used LC/MS/MS, peptide arrays, and scanning alanine mutagenesis to determine the specific residues of TTR that are involved in binding to beta-amyloid. Strikingly, we have observed a strong correlation between increased binding to beta-amyloid, and reduced quaternary stability of TTR. We are characterizing in detail the effect of TTR (wt and mutants) on beta-amyloid aggregation. Finally, in collaboration with Dr. Jeff Johnson, we are examining the effect of various TTR mutants on beta-amyloid toxicity, in an effort to determine the features of TTR that regulate beta-amyloid toxicity.

Beta-amyloid and transthyretin: is there a natural anti-Alzheimer's drug?

243rd National Meeting (2012)

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