Toxic species in amyloid disorders: Oligomers or mature fibrils

Abstract

Protein aggregation is the hallmark of several neurodegenerative disorders. These protein aggregation (fibrillization) disorders are also known as amyloid disorders. The mechanism of protein aggregation involves conformation switch of the native protein, oligomer formation leading to protofibrils and finally mature fibrils. Mature fibrils have long been considered as the cause of disease pathogenesis; however, recent evidences suggest oligomeric intermediates formed during fibrillization to be toxic. In this review, we have tried to address the ongoing debate for these toxic amyloid species. We did an extensive literature search and collated information from Pubmed (http://www.ncbi.nlm.nih.gov) and Google search using various permutations and combinations of the following keywords: Neurodegeneration, amyloid disorders, protein aggregation, fibrils, oligomers, toxicity, Alzheimer's Disease, Parkinson's Disease. We describe different instances showing the toxicity of mature fibrils as well as oligomers in Alzheimer's Disease and Parkinson's Disease. Distinct structural framework and morphology of amyloid oligomers suggests difference in toxic effect between oligomers and fibrils. We highlight the difference in structure and proposed toxicity pathways for fibrils and oligomers. We also highlight the evidences indicating that intermediary oligomeric species can act as potential diagnostic biomarker. Since the formation of these toxic species follow a common structural switch among various amyloid disorders, the protein aggregation events can be targeted for developing broad-range therapeutics. The therapeutic trials based on the understanding of different protein conformers (monomers, oligomers, protofibrils and fibrils) in amyloid cascade are also described.

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

“…Many recent studies provide a compelling support for the notion that soluble oligomeric Aβ peptides represent the most toxic species affecting multiple cellular mechanisms involved in AD including axonal trafficking (Verma et al, 2015). Moreover, formation of fibrils has been proposed to be protective by acting as a reservoir for toxic oligomers (Verma et al, 2015).…”

“…Many recent studies provide a compelling support for the notion that soluble oligomeric Aβ peptides represent the most toxic species affecting multiple cellular mechanisms involved in AD including axonal trafficking (Verma et al, 2015). Moreover, formation of fibrils has been proposed to be protective by acting as a reservoir for toxic oligomers (Verma et al, 2015). Therefore, to determine the effect of amyloid aggregates and fibrils on neurons and mitochondria in vivo, we applied TEM to examine the brain tissue in a mouse model of familial AD at two time points corresponding to early and late stages of disease development.…”

Glycodendrimers as Potential Multitalented Therapeutics in Alzheimer’s Disease

“…The formation of insoluble Aβ fibril follows a nucleation-dependent polymerization mechanism ( Figure 2) as described [28]. The formation of soluble Aβ oligomers in vivo is largely unknown; it is believed that soluble Aβ oligomers may precede fibril formation [29] and are more toxic than mature Aβ fibrils [30].…”

Human DnaJB6 Antiamyloid Chaperone Protects Yeast from Polyglutamine Toxicity Separately from Spatial Segregation of Aggregates

“…While the presence of amyloid is almost always associated with disease pathology, it remains unclear if amyloid accumulation itself is toxic or instead represents an inert and possibly cytoprotective process. Particular attention has been placed on oligomers, low-molecular-weight multimers, as a causative agent of cell death (2)(3)(4). Amyloid generation is believed to occur through a two-step nucleation mechanism that can produce oligomers at both stages.…”