Structural basis for increased toxicity of pathological a?42:a?40 ratios in Alzheimer disease.

ABSTRACT: The ?-amyloid peptide (A?) 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?(42):A?(40) ratio of ?1:9. This ratio is often shifted to a higher percentage of A?(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?(40) and A?(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?(42):A?(40) ratios by several techniques. We show that A?(40) and A?(42) directly interact as well as modify the behavior of the other. The structures of monomeric and fibrillar assemblies formed from A?(40) and A?(42) mixtures do not differ from those formed from either of these peptides alone. Instead, the co-assembly of A?(40) and A?(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?(42):A?(40) in synaptotoxicity assays and in AD patients.

SUBMITTER: Pauwels K 

PROVIDER: S-EPMC3285338 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature