Enhanced Fibril Fragmentation of N‐Terminally Truncated and Pyroglutamyl‐Modified Aβ Peptides

Abstract

N-terminal truncation and pyroglutamyl (pE) formation are naturally occurring chemical modifications of the Aβ peptide in Alzheimer's disease. We show herein that these two modifications significantly reduce the fibril length and the transition midpoint of thermal unfolding of the fibrils, but they do not substantially perturb the fibrillary peptide conformation. This observation implies that the N terminus of the unmodified peptide protects Aβ fibrils against mechanical stress and fragmentation and explains the high propensity of pE-modified peptides to form small and particularly toxic aggregates.

N‐Terminally Truncated Amyloid‐β(11–40/42) Cofibrillizes with its Full‐Length Counterpart: Implications for Alzheimer's Disease

“…Although residues 1–10 are not thought to form hydrogen‐bonded strands in Aβ (1–40) or Aβ (1–42) fibers, it is clear they contribute to fiber stability and resistance to mechanical shear forces. A similar tendency to fragment has been reported for another N‐terminally truncated form of Aβ, consisting of residues 4–40 . We also addressed the possibility that loss of the ten N‐terminal residues may modulate the formation of prefibrillar assemblies.…”

Modified amyloid variants in pathological subgroups of β‐amyloidosis

“…The simultaneous presence of truncated forms of A β other than A β N3pE and A β pS8 in B‐CAA stage 1 cerebrovascular A β deposits, however, could not be excluded. Additional to the aggregation‐promoting effect, phosphorylation, and pyroglutamination also affect the proteolytic degradation of A β monomers and the stability of A β aggregates . Thus, pyroglutamination could potentially favor further phosphorylation and, thereby, increase the stability of A β aggregates, and exaggerate A β aggregation.…”

Unmodified and pyroglutamylated amyloid β peptides form hypertoxic hetero‐oligomers of unique secondary structure

“…Conversely, Ab and AbpE have been reported to exert similar toxic effects on neurons [47,50,51]. Conflicting data have also been reported regarding b-sheet propensities and aggregation rates of Ab and AbpE [40][41][42][43][44][45][46][47][48][49][50]. Moreover, although the neurotoxic effect in brain tissue is exerted by heterogeneous assemblies of multiple forms of Ab, including Ab 1-42 and Ab pE3-42 [2,10,12,17], most structural and functional studies have been conducted on individual Ab species.…”

“…AbpE was shown to have a higher tendency toward formation of b-sheet aggregates, possibly promoting aggregation of Ab by a seeding mechanism [21,[40][41][42][43] and to be hypertoxic to neuronal cells [18][19][20][21]. Ab pE3-40 in trifluoroethanol/water environment had an increased tendency toward bsheet formation and fibrillization compared to Ab 1-40 [44,45], as well as higher susceptibility to mechanical stress and fragmentation of the fibrils [46]. These reports have been challenged by other studies, arguing that AbpE assemblies have similar content of b-sheet structure, are more resistant to fibrillogenesis [47][48][49][50], and exert cytotoxic effect similar to that of unmodified Ab [47,50,51].…”