Pyroglutamate‐Modified Amyloid β (11‐ 40) Fibrils Are More Toxic than Wildtype Fibrils but Structurally Very Similar

Abstract

The morphology, structure, and dynamics of mature amyloid β (Aβ) fibrils formed by the Aβ variant, which is truncated at residue 11 and chemically modified by enzymatic pyroglutamate formation (pGlu -Aβ(11-40)), was studied along with the investigation of the toxicity of these Aβ variants to neurons and astrocytes. The fibrils of pGlu -Aβ (11-40) were more toxic than wildtype Aβ (1-40) and the longer pGlu3-Aβ (3-40) especially at higher concentration, whereas the overall morphology was quite similar. The secondary structure of pGlu -Aβ (11-40) fibrils shows the typical two β-strands connected by a short turn as known for mature fibrils of Aβ (1-40) and also pGlu -Aβ (3-40). Further insights into tertiary contacts exhibit some similarities of pGlu -Aβ (11-40) fibrils with wildtype Aβ (1-40), but also a so far not described contact between Gly and Ile . This highlights the biological importance of chemical modifications on the molecular structure of Aβ.

Structural characteristics of oligomers formed by pyroglutamate-modified amyloid β peptides studied by solid-state NMR

“…Differences in the chemical shift values can also be observed for Phe 19 . Here, some unusual values were reported for the mature fibrils of pGlu 3 -Ab(3-40) (two signals) 44 and pGlu 11 -Ab(11-40), 45 therefore, here the values for the oligomers of these peptides match with those for wild type Ab(1-40) fibrils. 59 For a further comparison between oligomers of this study and the respective mature fibrils Fig.…”

“…3 as differences to the random coil values (taken from literature 58 ) for pGlu 3 -Ab and pGlu 11 -Ab oligomers. For comparison, also the chemical shift data for the mature fibrils of the respective peptides 44,45 are plotted into the same diagrams. According to the chemical shift values, the differences between oligomers and mature fibrils with regard to their secondary structure are rather small for both pyroglutamate modified peptides.…”

“…35 Interestingly, the structural features of the mature fibrils formed by these pyroglutamate-modified peptides have been found to be very similar compared to WT-Ab. 44,45 In fact, most modified and/or mutated Ab peptides that exhibit a much altered cytotoxic characteristics 46 show relatively mild structural alterations in the mature fibrillary state compared to the WT. [47][48][49][50] Although the exact mechanism how oligomeric Ab peptides exert their toxic potential to neurons remains speculative, it is clear that the structural features of these aggregates must differ from those of mature fibrils.…”

The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation

“…Indeed, N-terminal mutations that affect the charge of this region are known to modify amyloid beta fibril formation. Such mutations include amino acid changes (48,49), post-translational modifications (50) and truncations of the protein (19,(51)(52)(53). In addition, a number of residues in the N-terminus of amyloid beta can bind metal cationsincluding Cu 2+ and Zn 2+which also accelerate amyloid beta aggregation through mechanisms that are currently unresolved (54)(55)(56)(57).…”

Advancements of the sFIDA method for oligomer‐based diagnostics of neurodegenerative diseases

“…Aβ peptides are either 40 or 42 amino acid residues long, in addition, N‐terminal truncation and pyroglutamate (pGlu) formation of residue E3 and E11 may occur, which affects structure and toxicity. Although Aβ 1‐42 is more neurotoxic than Aβ 1‐40 , pGlu 11 ‐Aβ even exceeds the neurotoxicity of Aβ 1‐42 . As a further consequence, Aβ aggregates are heterogeneous and polymorphic , and even for amyloid fibrils grown from homogeneous monomer solutions in vitro the structure and supramolecular organization depends critically on the exact fibrillation conditions such as pH, ionic strength and stirring of the solution during fibril growth.…”