Quantification of N-terminal amyloid-β isoforms reveals isomers are the most abundant form of the amyloid-β peptide in sporadic Alzheimer's disease

Plaques that characterize Alzheimer's disease accumulate over 20 years as a result of decreased clearance of amyloid-beta peptides. Such long-lived peptides are subjected to multiple post-translational modifications, in particular isomerization. Using liquid chromatography ion mobility separations mass spectrometry, we characterized the most common isomerized amyloid-beta peptides present in the temporal cortex of sporadic Alzheimer's disease brains. Quantitative assessment of amyloid-beta N-terminus revealed that > 80% of aspartates (Asp-1 and Asp-7) in the N-terminus was isomerized, making isomerization the most dominant posttranslational modification of amyloid-beta in Alzheimer's disease brain. Total amyloid-beta(1-15) was similar to 85% isomerized at Asp-1 and/or Asp-7 residues, with only 15% unmodified amyloid-beta(1-15) left in Alzheimer's disease. While amyloid-beta(4-15) the next most abundant N-terminus found in Alzheimer's disease brain, was only similar to 50% isomerized at Asp-7 in Alzheimer's disease. Further investigations into different biochemically defined amyloid-beta-pools indicated a distinct pattern of accumulation of extensively isomerized amyloid-beta in the insoluble fibrillar plaque and membrane-associated pools, while the extent of isomerization was lower in peripheral membrane/vesicular and soluble pools. This pattern correlated with the accumulation of aggregation-prone amyloid-beta(42) in Alzheimer's disease brains. Isomerization significantly alters the structure of the amyloid-beta peptide, which not only has implications for its degradation, but also for oligomer assembly, and the binding of therapeutic antibodies that directly target the N-terminus, where these modifications are located.

Automated summary

Plaques in Alzheimer's disease brains accumulate due to decreased clearance of amyloid-beta peptides which undergo extensive isomerization, particularly at the Asp-1 and Asp-7 residues. Isomerization significantly alters the structure of the peptide, affecting its degradation, oligomer assembly, and the binding of therapeutic antibodies. The accumulation of extensively isomerized amyloid-beta is correlated with the presence of aggregation-prone amyloid-beta(42) in Alzheimer's disease brains.