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[摘要]：beta-Amyloid (A beta) is the main protein component of the amyloid plaques associated with Alzheimer's disease. Transthyretin (TTR) is a homotetramer that circulates in both blood and cerebrospinal fluid. Wild-type (wt) TTR amyloid deposits are linked to senile systemic amyloidosis, a common disease of aging, while several TTR mutants are linked to familial amyloid polyneuropathy. Several recent studies provide support for the hypothesis that these two amyloidogenic proteins interact, and that this interaction is biologically relevant. For example, upregulation of TTR expression in Tg2576 mice was linked to protection from the toxic effects of A beta deposition [Stein, T. D., and Johnson, J. A. (2002) J. Neurosci. 22, 7380-7388]. We examined the interaction of A beta with wt TTR as well as two mutants: F87M/L110M, engineered to be a stable monomer, and T119M, a naturally occurring mutant with a tetrameric stability higher than that of the wild type. On the basis of enzyme-linked immunoassays as well as cross-linking experiments, we conclude that A beta monomers bind more to TTR monomers than to TTR tetramers. The data further suggest that TTR tetramers interact preferably with A beta aggregates rather than A beta monomers. Through tandem mass spectrometry analysis of cross-linked TTR-A beta fragments, we identified the A strand, in the inner beta-sheet of TTR, as well as the EF helix, as regions of TTR that are involved with A beta association. Light scattering and electron microscopy studies demonstrate that the outcome of the TTR-A beta interaction strongly depends on TTR quaternary structure. While TTR tetramers may modestly enhance aggregation, TTR monomers decidedly arrest A beta aggregate growth. These data provide important new insights into the nature of TTR-A beta interactions. Such interactions may regulate TTR-mediated protection against A beta toxicity. |
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