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

ABSTRACT: Amyloid-beta (Aβ) plays a key role in the pathogenesis of Alzheimer’s disease (AD), but little is known about the proteoforms present in human AD brain. We used high-resolution mass spectrometry to analyze intact, undigested Aβ from purified soluble aggregates and insoluble material in brains of 6 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 Aβ. We found a diversity of Aβ peptides, with 26 unique proteoforms including various N- and C-terminal truncations. N- and C-terminal truncations comprised 73% and 30%, respectively, of the number of Aβ proteoforms detected. The Aβ 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 Aβ comprised the minority of the number of identified proteoforms (15.3%) and did not distinguish between the soluble and more insoluble aggregates. The relative abundance of many truncated Aβ proteoforms did not correlate with post-mortem interval, suggesting they are not artefacts. This heterogeneity of Aβ proteoforms deepens our understanding of AD and offers many new avenues for investigation into pathological mechanisms of the disease, with implications for therapeutic development.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Regional Part Of Nervous System

DISEASE(S): Alzheimer's Disease

SUBMITTER: Norelle Wildburger  

LAB HEAD: David L. Brody

PROVIDER: PXD006552 | Pride | 2017-08-28

REPOSITORIES: Pride