Increased Secondary Nucleation Underlies Accelerated Aggregation of the Four-Residue N-Terminally Truncated Aβ42 Species Aβ5–42

Abstract

Aggregation of the amyloid-β (Aβ) peptide into plaques is believed to play a crucial role in Alzheimer's disease. Amyloid plaques consist of fibrils of full length Aβ peptides as well as N-terminally truncated species. β-Site amyloid precursor protein-cleaving enzyme (BACE1) cleaves amyloid precursor protein in the first step in Aβ peptide production and is an attractive therapeutic target to limit Aβ generation. Inhibition of BACE1, however, induces a unique pattern of Aβ peptides with increased levels of Nterminally truncated Aβ peptides starting at position 5 (Aβ5-X), indicating that these peptides are generated through a BACE1-independent pathway. Here we elucidate the aggregation mechanism of Aβ5-42 and its influence on full-length Aβ42. We find that, compared to Aβ42, Aβ5-42 is more aggregation prone and displays enhanced nucleation rates. Aβ5-42 oligomers cause non-specific membrane disruption to similar extent as Aβ42 but appear at earlier time points in the aggregation reaction. Noteworthy, this implies similar toxicity of Aβ42 and Aβ5-42 and the toxic species are generated faster by Aβ5-42. The increased rate of secondary nucleation on the surface of existing fibrils originates from a higher affinity of Aβ5-42 monomers for fibrils, as compared to Aβ42: an effect that may be related to the reduced net charge of Aβ5-42. Moreover, Aβ5-42 and Aβ42 peptides coaggregate into heteromolecular fibrils and either species can elongate existing Aβ42 or Aβ5-42 fibrils but Aβ42 fibrils are more catalytic than Aβ5-42 fibrils. Our findings highlight the importance of the N-terminus for surface-catalyzed nucleation and thus the production of toxic oligomers.

The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis

“…To date, four BACEi drugs evaluated in late‐stage trials showed cognitive worsening during the treatment 41. One potential explanation for this finding is that alternate forms of N‐terminally truncated Aβ may be produced from APP in a β‐secretase–independent pathway, as recently reported by two groups 52–54. These alternate Aβ peptides were reported to form highly toxic Aβ oligomers 54.…”

“…41 One potential explanation for this finding is that alternate forms of N-terminally truncated A may be produced from APP in a -secretase-independent pathway, as recently reported by two groups. [52][53][54] These alternate A peptides were reported to form highly toxic A oligomers. 54 Therefore, A oligomer assays for A 40 and A 42 in BACEi studies may not correlate with clinical benefit for this class of drugs.…”

“…[52][53][54] These alternate A peptides were reported to form highly toxic A oligomers. 54 Therefore, A oligomer assays for A 40 and A 42 in BACEi studies may not correlate with clinical benefit for this class of drugs.…”

Cross-talk between individual phenol soluble modulins inS. aureusbiofilm formation

“…The initial increase in aggregate mass was measured through linear fits to the early points of the aggregation process, Fig. S3a, S3c, S3e and S3g [29,30]. The estimated elongation rate constant for PSMα1 and PSMβ2 were found to be 0.2 mM/h 2 and 0.5 mM/h 2 respectively, differing by a factor of ~2, which is insignificant.…”

ADSoluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer’s disease progression

“…To gain insight into the composition of the soluble aggregates responsible for the observed membrane permeabilisation, we employed an Aβ-specific antibody (Nb3) previously shown to counteract the toxicity induced by soluble aggregates of full length as well as N-terminally truncated Aβ both in vitro 16,23 and AD CSF 19 . We found that Nb3, which recognises amino acids 17-28 of the Aβ sequence, was able to significantly reduce the aggregate-induced membrane permeabilisation for both AD and MCI ( Fig.…”