Aβ42 Neurotoxicity Is Mediated by Ongoing Nucleated Polymerization Process Rather than by Discrete Aβ42 Species

Abstract

Aggregation of amyloid-␤ (A␤)2 peptides and deposition into neuritic plaques are hallmark features of Alzheimer disease (AD) neuropathology (1, 2). Therefore, research efforts during the past 3 decades have focused on elucidating the mechanisms of A␤ fibrillization, identifying toxic species, and developing strategies to inhibit and/or reverse A␤ amyloid formation and toxicity in vivo (3,4).A␤ peptides are produced as soluble monomers (5, 6) and undergo oligomerization and amyloid fibril formation via a nucleation-dependent polymerization process (7,8). During the course of in vitro A␤ fibril formation, various nonfibrillar aggregation intermediates, collectively called soluble oligomers or protofibrils, have been shown to precede the emergence of fibrils. Increasing evidence from various sources points to A␤ oligomers/protofibrils as putative toxic species in AD pathogenesis and suggests that these species are potential therapeutic targets for treating AD (reviewed in Refs. 9, 10). Although the toxic oligomer hypothesis has emerged as one of the major current working hypotheses in AD research, the development of effective diagnostic tools and therapies on the basis of this hypothesis has yet to be realized (11-13). This is partially due to the fact that identification of a single toxic A␤ species that correlates with AD progression and severity remains elusive. Furthermore, the exact mechanisms by which these species contribute to A␤ toxicity in vivo and the nature of the toxic species are not yet fully understood. Recent evidence suggests that accelerating the process of A␤ fibrillization greatly enhances A␤ toxicity in vitro (14) and the spread of amyloid pathology in vivo (15-17).Despite significant efforts by different groups to isolate specific intermediates along the amyloid formation pathway (12, 18 -22), the inherent heterogeneity of the process and metastable nature of A␤ oligomers (11-13) have precluded the isolation of a single toxic species. Unless covalently crosslinked (23), A␤ oligomers do not exist as stable entities, i.e. they evolve into higher order aggregates and, if they are onpathway intermediates, convert into fibrils (19). Therefore, it is plausible to assume that the structural dynamics of oligomers and factors that govern their interconversion and/or growth might influence some of the disease-related cytotoxic effects of A␤. In other words, an ongoing polymerization

Ultrasensitive Measurement of Ca2+ Influx into Lipid Vesicles Induced by Protein Aggregates

“…Several possible mechanisms of cellular damage have been identified with relative contributions that depend on both the concentrations and the types of aggregates present 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. The aggregation process that results in the formation of oligomers may contribute to cellular damage 12, 13, 14, 15. Some of these mechanisms are thought to involve specific binding to receptors on the cell membrane1, 5, 9 while others appear to be the consequence of non‐specific membrane disruption 1, 3, 5, 9, 16.…”

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

“…Although the toxic species is still poorly defined, there is growing consensus that the process, rather than the end product, of amyloid formation is the main culprit in amyloid toxicity [31][32][33][34]. Small oligomers of Aβ secreted from cell lines that overproduce Aβ 42 inhibit long-term potentiation in hippocampal synaptic transmission [32] and induces neuronal toxicity in mice [35].…”

“…Small oligomers of Aβ secreted from cell lines that overproduce Aβ 42 inhibit long-term potentiation in hippocampal synaptic transmission [32] and induces neuronal toxicity in mice [35]. Oligomeric forms of αS and Aβ inhibit mitochondrial activity [31,36]. Toxicity of Aβ 42 aggregates ebbs as monomers are depleted, but can be restored by the addition of fresh monomeric protein [31].…”

“…Oligomeric forms of αS and Aβ inhibit mitochondrial activity [31,36]. Toxicity of Aβ 42 aggregates ebbs as monomers are depleted, but can be restored by the addition of fresh monomeric protein [31].…”

“…Multiple lines of evidence suggest that oligomeric intermediate stages of the amyloid cascade are the main culprits for the toxicity of misfolded proteins [31,51]. Different strategies can be applied to reduce the amount of toxic oligomers (Fig.…”