[摘要]：The beta-amyloid peptide (A beta) is directly related to neurotoxicity in Alzheimer disease (AD). The two most abundant alloforms of the peptide co-exist under normal physiological conditions in the brain in an A beta(42):A beta(40) ratio of similar to 1:9. This ratio is often shifted to a higher percentage of A beta(42) in brains of patients with familial AD and this has recently been shown to lead to increased synaptotoxicity. The molecular basis for this phenomenon is unclear. Although the aggregation characteristics of A beta(40) and A beta(42) individually are well established, little is known about the properties of mixtures. We have explored the biophysical and structural properties of physiologically relevant A beta(42): A beta(40) ratios by several techniques. We show that A beta(40) and A beta(42) directly interact as well as modify the behavior of the other. The structures of monomeric and fibrillar assemblies formed from A beta(40) and A beta(42) mixtures do not differ from those formed from either of these peptides alone. Instead, the co-assembly of A beta(40) and A beta(42) influences the aggregation kinetics by altering the pattern of oligomer formation as evidenced by a unique combination of solution nuclear magnetic resonance spectroscopy, high molecular weight mass spectrometry, and cross-seeding experiments. We relate these observations to the observed enhanced toxicity of relevant ratios of A beta(42):A beta(40) in synaptotoxicity assays and in AD patients.
