Amyloid Cross-Seeding: Mechanism, Implication, and Inhibition

Abstract

Most neurodegenerative diseases such as Alzheimer's disease, type 2 diabetes, Parkinson's disease, etc. are caused by inclusions and plaques containing misfolded protein aggregates. These protein aggregates are essentially formed by the interactions of either the same (homologous) or different (heterologous) sequences. Several experimental pieces of evidence have revealed the presence of cross-seeding in amyloid proteins, which results in a multicomponent assembly; however, the molecular and structural details remain less explored. Here, we discuss the amyloid proteins and the cross-seeding phenomena in detail. Data suggest that targeting the common epitope of the interacting amyloid proteins may be a better therapeutic option than targeting only one species. We also examine the dual inhibitors that target the amyloid proteins participating in the cross-seeding events. The future scopes and major challenges in understanding the mechanism and developing therapeutics are also considered. Detailed knowledge of the amyloid cross-seeding will stimulate further research in the practical aspects and better designing anti-amyloid therapeutics.

Keywords: aggregation; amyloid proteins; cross-seeding; dual inhibition; fibrillation; protein misfolding diseases.

Figure 3

Domain structure of tau protein. The N-terminal domain, proline-rich region (PRR), microtubule-binding region (MTBR), and C-terminal region (CTD) are shown. The PHF aggregate from 308–380 amino acids (in green) of tau protein solved by cryo-EM (PDB ID: 7NRQ) [91] shows the assembly of tau in the diseased fibril phase.

Figure 1

Amyloid seeding and aggregation. The addition of preformed seeds reduces the lag phase leading to faster aggregation. The seeds can be homologous or heterologous. Homologous seeds, which have the same nature as the existing nuclei, lead to homologous seeding, whereas the heterologous seeds differ from the initial nuclei and lead to heterologous or cross-seeding.

Figure 2

Human APP cleavage pathway. The human APP undergoes proteolytic cleavage in two different pathways: amyloidogenic and non-amyloidogenic. In the non-amyloidogenic pathway, the α-secretases cleave within the Aβ domain to form the α-C terminal fragments (CTFα), and the N-terminal soluble APP (sAPPα). The CTFα is subsequently cleaved by γ-secretase to form P3 and APP intracellular domain (AICD). In the amyloidogenic pathway, the β-secretase initially cleaves APP to form β-C-terminal fragments (CTFβ) and N-terminal-soluble APP (sAPPβ). The CTFβ is then cleaved by γ-secretase to form extracellular Aβ and AICD. The arrangement of Aβ40 (red) (PDB ID: 6TI5) [65] and Aβ42 (green) (PDB ID: 2BEG) [66] in the fibrillar phase are shown on the right. The β-sheet structure of the peptide and the parallel direction can be observed in the figure.

Figure 4

Domain structure of the α-syn protein. The lipid-binding N-terminal domain (NTD) is represented in orange, while the non-Aβ component (NAC) region necessary for the aggregation of α-syn protein is in blue. The C-terminal domain (CTD) of α-syn protein is represented in green. On top, the arrangement of α-syn protein in fibrillar form is shown (PDB ID: 6FLT) [27].

Figure 5

Schematic representation of hIAPP aggregation kinetics. The sigmoidal curves house the different forms: monomer, oligomer, protofibrils, and fibrils of hIAPP that are formed at various phases with time. The representation is shown for kinetics without seeding. The structures of different forms of hIAPP are shown (PDB IDs: 2KIB and 6VW2) [110,111].

Figure 6

Domain structure of PrP protein. The signal peptide that guides the PrP protein is represented in red, with the octapeptide in orange. The globular C-terminal domain (CTD) with α-helices and β-sheets are shown in purple. The hydrophobic domain (HD) between the octapeptide and the CTD is colored in blue. The fibril form of human PrP is shown at the top (PDB ID: 6UUR) [126].

Figure 7

General mechanism of dual inhibitors of cross-seeding: (A) in the absence of an inhibitor, protein A acts as a seed and facilitates the cross-seeding of protein B; (B) in the presence of a dual inhibitor, the toxicity of the amyloid fibers of protein A is reduced, and the cross-seeding of protein B is also inhibited.