Localization of A11‐reactive oligomeric species in prion diseases

Abstract

We confirm that intracellular and extracellular A11-reactive species are present in situ in sCJD cases and GSS, and that immunoreactivity for A11 and Prp(Sc) overlaps. We argue that the A11-reactive species are indeed composed of oligomeric Prp(Sc), and suggest that the toxic effects of Prp(Sc) oligomers could be related to the generic oligomeric conformation recognized by A11.

Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

“…311 Most oligomeric states had larger α-helical than β-sheet content, and in about 5% of the simulations β-barrel conformations were formed by pentamers and hexamers. Furthermore, the same research group reported that five fragments of amyloidogenic peptides, namely the cytotoxic hIAPP (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) and its Ser20Gly mutant as well as hIAPP (22)(23)(24)(25)(26)(27)(28), Aβ (16)(17)(18)(19)(20)(21)(22) and α-nuclein (68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78), formed oligomers with β-barrel content in DMD simulations while two non-toxic fragments (hIAPP (15)(16)(17)(18)(19)(20)(21)(22)(23)…”

“…The result confirms interaction between the peptides, but as found in vitro, homologous seeding is preferred over heterologous seeding . In the past, for many years, the hypothesis that the killer of neurons (AD) or β-cells (T2D) were the insoluble amyloid fibrils (amyloid hypothesis) has been supported. ,− Subsequently, the hypothesis of toxic oligomers was advanced, where the toxicity of Aβs or hIAPP is due to the oligomers, transient species that precede the fibrillar state. ,− Experimental data have shown that polyclonal antibodies prepared by Aβ 40 , can recognize not only the toxic oligomers of Aβ 40 but also the oligomers of a-synuclein, lysozyme, insulin, IAPP, prion protein, and many other proteins. ,,− The same result was obtained using IAPP oligomeric preparation, rather than Aβ mimic. De novo designed peptides derived from hIAPP interacting with Aβ form colloid-like oligomers having β-like structures .…”

“…21,[61][62][63] Subsequently, the hypothesis of toxic oligomers was advanced, where the toxicity of Aβs or hIAPP is due to the oligomers, transient species that precede the fibrillar state. 61,[64][65][66][67][68] Experimental data have shown that polyclonal antibodies prepared by Aβ40, can recognize not only the toxic oligomers of Aβ40 but also the oligomers of a-synuclein, lysozyme, insulin, IAPP, prion protein, and many other proteins 62,63,[69][70][71][72] . The same result was obtained using IAPP oligomeric preparation, rather than Aβ mimic.…”

Selective vulnerability to neurodegenerative disease: the curious case of Prion Protein

“…Although the aggregates found in histological sections of brains affected by different neurodegenerative diseases have different shapes and tinctorial properties, they seem to develop from a common pathway, as demonstrated by their universal reactivity with a pair of antibodies generated against an Alzheimer’s disease (AD)-related peptide (Kayed et al, 2003). The antibodies react with either small oligomeric forms or higher-order aggregates from several neurodegenerative disease-related proteins, including prion diseases (PrDs) (Aidt et al, 2013), indicating that the misfolded proteins share common conformational transition states (Glabe, 2006; Kayed et al, 2003). Inherited mutations in the genes encoding many of these proteins are causally linked to familial forms of neurodegeneration, further highlighting the importance of the malformed proteins for disease development.…”

Application of biomaterials for the detection of amyloid aggregates

“…29 In a recent study, A11-reactive oligomeric species were found in the brain of a patient suffering from sporadic Creutzfeldt-Jakob disease. 31 However, because of the diverse structures and sizes of oligomers, 6 the development of antibodies specific to each oligomer is still necessary.…”