Abstract
Plaques that characterize Alzheimer’s disease accumulate over 20 years as a result of decreased clearance of amyloid-β 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-β peptides present in the temporal cortex of sporadic Alzheimer’s disease brains. Quantitative assessment of amyloid-β N-terminus revealed that > 80% of aspartates (Asp-1 and Asp-7) in the N-terminus was isomerized, making isomerization the most dominant post-translational modification of amyloid-β in Alzheimer’s disease brain. Total amyloid-β1–15 was ∼85% isomerized at Asp-1 and/or Asp-7 residues, with only 15% unmodified amyloid-β1–15 left in Alzheimer’s disease. While amyloid-β4–15 the next most abundant N-terminus found in Alzheimer’s disease brain, was only ∼50% isomerized at Asp-7 in Alzheimer’s disease. Further investigations into different biochemically defined amyloid-β-pools indicated a distinct pattern of accumulation of extensively isomerized amyloid-β 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-β42 in Alzheimer’s disease brains. Isomerization significantly alters the structure of the amyloid-β 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.
Highlights
Neuropathology and amyloid-b (Ab) positron emission tomography (PET) studies indicate that the accumulation of Ab in sporadic Alzheimer’s disease brain begins more than 20 years before the onset of clinical symptoms.[1,2] Evidence supports that this accumulation is a result of decreased clearance and not a change in the production of Ab in sporadic Alzheimer’s disease.[3,4] The subtle 2–5% decrease in its clearance results in total accumulation of $6.5 mg Ab in the brain over the 20 year time span[2,5] compared to 1.7 mg in age-matched control tissue
Previous reports characterizing stereoisomers of synthetic Ab have demonstrated that isomerization at position Asp-1 and Asp-7 is frequent.[23,38,52]
Neither the extent of isomerization of Asp-1 and Asp-7 residues in Ab1–15, Ab2–15, Ab3Glu-15 and Ab4–15 have been directly measured in human brain nor has a systematic study been conducted using ion mobility to determine the effect of isomerization on the structure of these peptides in the gas phase
Summary
Neuropathology and amyloid-b (Ab) positron emission tomography (PET) studies indicate that the accumulation of Ab in sporadic Alzheimer’s disease brain begins more than 20 years before the onset of clinical symptoms.[1,2] Evidence supports that this accumulation is a result of decreased clearance and not a change in the production of Ab in sporadic Alzheimer’s disease.[3,4] The subtle 2–5% decrease in its clearance results in total accumulation of $6.5 mg Ab in the brain over the 20 year time span[2,5] compared to 1.7 mg in age-matched control tissue. Several questions regarding the Ab-amyloid hypothesis[6] remain unanswered, including what leads to the decrease in clearance and what triggers the aggregation of Ab into extracellular plaques[7] along with intracellular tau-reactive neurofibrillary tangles.[8] The impairment in the clearance increases the half-life of the Ab polypeptide and the process of amyloidosis in Alzheimer’s disease entombs the peptide for decades, making it a long-lived peptide. The prolonged time frame of amyloidosis is a common feature across multiple neurodegenerative diseases,[9,10] predisposing the polypeptide chains to undergo multiple spontaneous non-enzymatic post-translational modifications (PTMs), which can render them resistant to normal cellular proteolysis mechanisms.[11,12]
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