Proteomics

Dataset Information

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


ABSTRACT: Amyloid-beta (Aβ) plays a key role in the neuropathogenesis of Alzheimer’s disease, but little is known about the proteoforms (i.e., all protein variants of a single gene including post-translational modifications and sequence variants) present in human AD brain. We used high-resolution mass spectrometry to analyze intact, whole Aβ from soluble and insoluble aggregates in brains of 6 cases with severe dementia and pathologically confirmed Alzheimer’s disease. We found an extraordinary diversity of Aβ peptides totaling 91 unique proteoforms including various N- and C-terminal truncations, 17 different types of post-translational modifications (PTMs), and remarkably 5 amino acid variants in the peptide sequence never before described. Ratios of Aβ proteoforms did not distinguish between soluble and insoluble aggregates, but four individual Aβ proteoforms, three in the insoluble and one in the soluble fraction, were markedly increased when compared across aggregates. Such heterogeneity of the Aβ peptide both deepens our understanding of AD, but perhaps also warrants pause and consideration in our investigation into pathological mechanisms of the disease and therapeutic development.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain Gray Matter, Brain, Brain White Matter

DISEASE(S): Alzheimer's Disease

SUBMITTER: Norelle Wildburger  

LAB HEAD: David Brody

PROVIDER: PXD005119 | Pride | 2017-09-04

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
1200F_Oligomer_tech-rep1.mgf Mgf
1200F_Oligomer_tech-rep1.raw Raw
1200F_Oligomer_tech-rep1_analyticalrep2.mgf Mgf
1200F_Oligomer_tech-rep1_analyticalrep2.raw Raw
1200F_Plaque_tech-rep1.mgf Mgf
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Publications


Amyloid-beta (Aβ) 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 Aβ 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 Aβ. We found a diversity of Aβ peptides, with 26 unique proteofo  ...[more]

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