Shedding Light on Alzheimer's β‐Amyloid Aggregation with Chemical Tools

Protein aggregation into amyloid fibrils in vivo is associated with cell damage and the pathogenesis of a number of incurable cell degenerative diseases including Alzheimer’s disease (AD), spongiform encephalopathies, and type II diabetes (T2D). 2] The amyloid deposits in each of the diseases consist of a disease-specific protein or polypeptide. However, similar molecular pathways appear to be involved in the aggregation and cell toxicity of the different amyloidogenic proteins. 2] Amyloid fibrils have been historically considered to cause, or at least to be directly associated with, cell degeneration in AD and the other amyloid diseases mainly because of to their colocalization with degenerated cells in vivo. 3] Therefore, understanding the molecular mechanism of amyloid formation and related cytotoxicity has been a major research focus, and well-established laboratory methods for the detection and quantification of amyloid are available. 5] Earlier in vitro studies with different amyloidogenic polypeptides suggested that amyloid formation proceeds through nucleation-dependent protein polymerization (NP; Figure 1, top). Accordingly, and in analogy to protein crystallization, the formation of small amounts of an oligomeric “nucleus” is the rate-determining step, as it requires a number of thermodynamically unfavorable self-assembly steps. Amyloid fibril growth occurs thereafter rapidly by the addition of monomers at several “sites” of the nucleus; this is a thermodynamically favorable process. Thus, fibrils form through a two-step process that consists of nucleation and growth phases, although significant amounts of stable assemblies are not expected to form in the fibril prenucleation phase. Importantly, in vivo amyloid formation in the brains of mouse models of AD has been found to be exogenously induced by seeding with AD brain extracts, thus providing evidence for an in vivo relevance of the NP mechanism to amyloid formation in AD. In the past two decades, however, data from a number of laboratories have suggested that significant amounts of soluble nonfibrillar oligomeric populations are present early (i.e. , before amyloid fibrils) in the amyloidogenesis pathways of different polypeptides. In this context, Lindquist and co-workers have proposed a modified form of NP, the “nucleated conformational conversion” (NCC) model, to describe the amyloidogenesis of the prion protein, Sup35. According to this model, amyloid nuclei and subsequently amyloid fibrils form by a conformational conversion of partially structured monomers that are part of structurally flexible oligomers (Figure 1, bottom). Thus, the NCC model includes oligomers as stable assembly intermediates in the fibril prenucleation phase. In the case of the Alzheimer’s disease b-amyloid peptide, Ab, various different prefibrillar oligomeric assemblies have been also identified and have been suggested to be cytotoxic. 10, 14–17] Most Figure 1. Schematic presentation of the amyloid fibril formation pathway through nucleation-dependent polymerization (NP; top) and nucleated conformational conversion (NCC; bottom). 8] The yellow circles around nuclei and nonfibrillar oligomers underline the important role of this species in NP and NCC.