Amyloid-beta oligomerization is associated with the generation of a typical peptide fragment fingerprint

作者：Rudinskiy Nikita; Fuerer Christophe; Demurtas Davide; Zamorano Sebastian; De Piano Cyntia; Herrmann Abigail G; Spires Jones Tara L; Oeckl Patrick; Otto Markus; Frosch Matthew P; Moniatte Marc; Hyman Bradley T; Schmid Adrien W^*

来源：Alzheimer's and Dementia, 2016, 12(9): 996-1013.

DOI：10.1016/j.jalz.2016.03.011

• Alzheimer's disease
• Aggregation
• Autocleavage
• Oligomers
• C-terminal amidation
• Mass spectrometry
• Selected reaction monitoring

Amyloid-beta (A beta) peptide oligomerization plays a central role in the pathogenesis of Alzheimer's disease (AD), and A beta oligomers are collectively considered an appealing therapeutic target for the treatment of AD. However, the molecular mechanisms leading to the pathologic accumulation of oligomers are unclear, and the exact structural composition of oligomers is being debated. Using targeted and quantitative mass spectrometry, we reveal site-specific A beta autocleavage during the early phase of aggregation, producing a typical A beta fragment signature and that truncated A beta peptides can form stable oligomeric complexes with full-length A beta peptide. We show that the use of novel anti-A beta antibodies raised against these truncated A beta isoforms allows for monitoring and targeting the accumulation of truncated A beta. fragments. Antibody-enabled screening of transgenic models of AD as well as human postmortem brain tissue and cerebrospinal fluid revealed that aggregation-associated A beta cleavage is a highly relevant clinical feature of AD.

• 出版日期2016-9