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

作者：Wildburger Norelle C^*; Esparza Thomas J; LeDuc Richard D; Fellers Ryan T; Thomas Paul M; Cairns Nigel J; Kelleher Neil L; Bateman Randall J; Brody David L^*

来源：Scientific Reports, 2017, 7(1): 9520.

DOI：10.1038/s41598-017-10422-x

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.

• 出版日期2017-8-25
• 单位西北大学