Applications of Mass Spectrometry in the Onset of Amyloid Fibril Formation: Focus on the Analysis of Early-Stage Oligomers

Amyloid fibril formation is a hallmark of diverse neurodegenerative and metabolic diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and type 2 diabetes mellitus (T2DM). Conventional diagnosis is based on the appearance of fibrils or plaques, while neglects the role of early-stage oligomers in the disease progression. Recent studies have uncovered that it is the early-stage oligomer, rather than the mature fibril, that greatly contributes cytotoxicity. The formation of oligomers involves complicate structural conversions and it is essential to investigate their conformational changes for a better understanding of aggregation mechanism. The coexistence of soluble early-stage oligomers, intermediates, and pre-fibril species makes it difficult to be differentiate by morphological methods, and only average structural information is provided as they lack the ability of separation. Therefore, mass spectrometry (MS) becomes an alternative technique that presents new and complementary insights into the onset of amyloid fibrils. This review highlights the hotspots and important achievements by MS in the field of amyloid formation mechanism, including the direct detection and differentiation of soluble oligomers (native MS), unambiguous identification of interacted sites involved in the onset of aggregation [hydrogen/deuterium exchange (HDX) and chemical cross-linking (CX)], and conformational switch that leads to fibrilization [collision cross section (CCS) regularity by ion mobility (IM)].