Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
School of Life Sciences, Proteomics Core Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Alzheimers Dement. 2016 Sep;12(9):996-1013. doi: 10.1016/j.jalz.2016.03.011. Epub 2016 Apr 26.
Amyloid-beta (Aβ) peptide oligomerization plays a central role in the pathogenesis of Alzheimer's disease (AD), and Aβ 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 Aβ autocleavage during the early phase of aggregation, producing a typical Aβ fragment signature and that truncated Aβ peptides can form stable oligomeric complexes with full-length Aβ peptide. We show that the use of novel anti-Aβ antibodies raised against these truncated Aβ isoforms allows for monitoring and targeting the accumulation of truncated Aβ fragments. Antibody-enabled screening of transgenic models of AD as well as human postmortem brain tissue and cerebrospinal fluid revealed that aggregation-associated Aβ cleavage is a highly relevant clinical feature of AD.
淀粉样蛋白-β（Aβ）肽寡聚化在阿尔茨海默病（AD）的发病机制中起核心作用，Aβ寡聚体被普遍认为是治疗 AD 的有吸引力的治疗靶点。然而，导致寡聚体病理性积累的分子机制尚不清楚，而且寡聚体的确切结构组成仍存在争议。使用靶向和定量质谱分析，我们揭示了在聚集的早期阶段 Aβ的特异性自动切割，产生典型的 Aβ片段特征，并且截断的 Aβ肽可以与全长 Aβ肽形成稳定的寡聚复合物。我们表明，使用针对这些截断的 Aβ亚型的新型抗 Aβ抗体可以进行监测和靶向截断的 Aβ片段的积累。针对 AD 的转基因模型以及人死后脑组织和脑脊液进行的抗体辅助筛选表明，与聚集相关的 Aβ切割是 AD 的一个高度相关的临床特征。
