Diversity of Amyloid-beta Proteoforms in the Alzheimer's Disease Brain

被引:123
作者
Wildburger, Norelle C. [1 ]
Esparza, Thomas J. [1 ]
LeDuc, Richard D. [2 ]
Fellers, Ryan T. [2 ]
Thomas, Paul M. [2 ]
Cairns, Nigel J. [1 ,3 ,4 ,5 ]
Kelleher, Neil L. [2 ,6 ,7 ]
Bateman, Randall J. [1 ,3 ,5 ]
Brody, David L. [1 ,5 ]
机构
[1] Washington Univ, Dept Neurol, Sch Med, 660 South Euclid Ave, St Louis, MO 63110 USA
[2] Northwestern Univ, Prote Ctr Excellence, Evanston, IL USA
[3] Knight Alzheimers Dis Res Ctr, Dept Neurol, 4488 Forest Pk Pkwy, St Louis, MO 63112 USA
[4] Dept Pathol & Immunol, 660 South Euclid Ave, St Louis, MO 63110 USA
[5] Hope Ctr Neurol Disorders, Dept Neurol, 660 South Euclid Ave, St Louis, MO 63110 USA
[6] Northwestern Univ, Dept Mol Biosci, Evanston, IL USA
[7] Northwestern Univ, Dept Chem, Evanston, IL USA
基金
美国国家卫生研究院;
关键词
MASS-SPECTROMETRY; PRECURSOR PROTEIN; LABEL-FREE; CEREBROSPINAL-FLUID; PEPTIDE; CORRELATE; QUANTITATION; DEPOSITION; DEMENTIA; COMPLEX;
D O I
10.1038/s41598-017-10422-x
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Amyloid-beta (A beta) plays a key role in the pathogenesis of Alzheimer's disease (AD), but little is known about the proteoforms present in AD brain. We used high-resolution mass spectrometry to analyze intact A beta from soluble aggregates and insoluble material in brains of six cases with severe dementia and pathologically confirmed AD. The soluble aggregates are especially relevant because they are believed to be the most toxic form of A beta. We found a diversity of A beta peptides, with 26 unique proteoforms including various N- and C-terminal truncations. N-and C-terminal truncations comprised 73% and 30%, respectively, of the total A beta proteoforms detected. The A beta proteoforms segregated between the soluble and more insoluble aggregates with N-terminal truncations predominating in the insoluble material and C-terminal truncations segregating into the soluble aggregates. In contrast, canonical A beta comprised the minority of the identified proteoforms (15.3%) and did not distinguish between the soluble and more insoluble aggregates. The relative abundance of many truncated A beta proteoforms did not correlate with post-mortem interval, suggesting they are not artefacts. This heterogeneity of A beta proteoforms deepens our understanding of AD and offers many new avenues for investigation into pathological mechanisms of the disease, with implications for therapeutic development.
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页数:9
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