Amyloid‐β Peptide Induces Prion Protein Amyloid Formation: Evidence for Its Widespread Amyloidogenic Effect

Abstract

Transmissible spongiform encephalopathy is associated with misfolding of prion protein (PrP) into an amyloid β-rich aggregate. Previous studies have indicated that PrP interacts with Alzheimer's disease amyloid-β peptide (Aβ), but it remains elusive how this interaction impacts on the misfolding of PrP. This study presents the first in vitro evidence that Aβ induces PrP-amyloid formation at submicromolar concentrations. Interestingly, systematic mutagenesis of PrP revealed that Aβ requires no specific amino acid sequences in PrP, and induces the misfolding of other unrelated proteins (insulin and lysozyme) into amyloid fibrils in a manner analogous to PrP. This unanticipated nonspecific amyloidogenic effect of Aβ indicates that this peptide might be involved in widespread protein aggregation, regardless of the amino acid sequences of target proteins, and exacerbate the pathology of many neurodegenerative diseases.

Alzheimer’s Disease “Non-amyloidogenic” p3 Peptide Revisited: A Case for Amyloid-α

“…Interestingly, the kinetic profile for p3 F20Y closely matched that of p3, while p3 F19Y exhibited a slightly attenuated onset of aggregation. This may indicate a favorable interaction between F19 and another residue, reinforced by the discovery that a F19P mutation abolishes Aβ aggregation . Moreover, our findings are supported by Bitan et al showing that truncations of residues 1–9 of Aβ do not inhibit oligomer formation .…”

“…This may indicate a favorable interaction between F19 and another residue, reinforced by the discovery that a F19P mutation abolishes Aβ aggregation. 54 Moreover, our findings are supported by Bitan et al showing that truncations of residues 1−9 of Aβ do not inhibit oligomer formation. 49 Aβ also formed similar assembly sizes in addition to faint signals corresponding to high-N structures (20−30 kDa).…”

microRNA‐425 loss mediates amyloid plaque microenvironment heterogeneity and promotes neurodegenerative pathologies

“…According to the amyloid cascade hypothesis, promoting the clearance of amyloid or reducing its aggregation has been the goals of preclinical and clinical studies for several decades (Mullard, 2016 ). Recently, numerous studies found that amyloid pathology can spread in the AD brain like prions (Honda, 2018 ; McAllister et al, 2020 ). This is not inconsistent with senile plaques influencing the brain microenvironment and facilitating more amyloid‐β production, aggregation and spreading.…”

Lysozyme Fibrils Alter the Mechanism of Insulin Amyloid Aggregation

“…Considering that previously reported cases analyzed the interaction of amyloid proteins that had the ability of coming into contact in vivo (alpha-synuclein, Tau, prion proteins, and amyloid-beta) [24,[28][29][30][31][32], it was interesting to examine if such amyloid crossinteractions can occur between proteins that do not share a localization. From these results, it is clear that the presence of lysozyme fibrils has a major impact on the aggregation mechanism of insulin.…”

“…There have been several studies displaying heterogenous cross-interactions of neurodegenerative disease-related amyloid proteins. It was shown that amyloid-beta aggregates are capable of inducing/enhancing the fibrilization of non-aggregated alpha-synuclein [24], Tau [28], and prion proteins [29]. Similarly, alpha-synuclein aggregates had a positive effect on Tau [30] and prion protein fibrilization [31].…”