Structural variation in amyloid-beta fibrils from Alzheimer's disease clinical subtypes

Article

关键词: ATOMIC-RESOLUTION STRUCTURE;    PRION STRAINS;    POLYMORPHISM;    MODEL;    MICE;   

DOI  :  10.1038/nature20814

来源: SCIE

【 摘 要 】

Aggregation of amyloid-beta peptides into fibrils or other self-assembled states is central to the pathogenesis of Alzheimer's disease. Fibrils formed in vitro by 40- and 42-residue amyloid-beta peptides (A beta 40 and A beta 42) are polymorphic, with variations in molecular structure that depend on fibril growth conditions(1-12). Recent experiments(1,13-16) suggest that variations in amyloid-beta fibril structure in vivo may correlate with variations in Alzheimer's disease phenotype, in analogy to distinct prion strains that are associated with different clinical and pathological phenotypes(17-19). Here we investigate correlations between structural variation and Alzheimer's disease phenotype using solid-state nuclear magnetic resonance (ssNMR) measurements on A beta 40 and A beta 42 fibrils prepared by seeded growth from extracts of Alzheimer's disease brain cortex. We compared two atypical Alzheimer's disease clinical subtypes-the rapidly progressive form (r-AD) and the posterior cortical atrophy variant (PCA-AD)-with a typical prolonged-duration form (t-AD). On the basis of ssNMR data from 37 cortical tissue samples from 18 individuals, we find that a single A beta 40 fibril structure is most abundant in samples from patients with t-AD and PCA-AD, whereas A beta 40 fibrils from r-AD samples exhibit a significantly greater proportion of additional structures. Data for A beta 42 fibrils indicate structural heterogeneity in most samples from all patient categories, with at least two prevalent structures. These results demonstrate the existence of a specific predominant A beta 40 fibril structure in t-AD and PCA-AD, suggest that r-AD may relate to additional fibril structures and indicate that there is a qualitative difference between A beta 40 and A beta 42 aggregates in the brain tissue of patients with Alzheimer's disease.

【 授权许可】

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