Alzheimer’s disease (AD) represents a progressive amyloidogenic disorder whose advancement is widely recognized to be connected to amyloid-β peptides and Tau aggregation. However, several other processes likely contribute to the development of AD and some of them might be related to protein-protein interactions. Amyloid aggregates usually contain not only single type of amyloid protein, but also other type of proteins and this phenomenon can be rationally explained by the process of protein cross-seeding and co-assembly. Amyloid cross-interaction is ubiquitous in amyloid fibril formation and so a better knowledge of the amyloid interactome could help to further understand the mechanisms of amyloid related diseases. In this review, we discuss about the cross-interactions of amyloid-β peptides, and in particular Aβ1-42, with other amyloids, which have been presented either as integrated part of Aβ neurotoxicity process (such as Tau) or conversely with a preventive role in AD pathogenesis by directly binding to Aβ (such as transthyretin, cystatin C and apolipoprotein A1). Particularly, we will focus on all the possible therapeutic strategies aiming to rescue the Aβ toxicity by taking inspiration from these protein-protein interactions.

Acyclic β-hairpins designed on oligomeric and fibril structures of Aβ_1–42 disrupt protein–protein interactions mediating amyloid β-peptide aggregation.

Natural compounds, such as plant and fruit extracts have shown neuroprotective effect against neurodegenerative diseases. It has been reported that several natural compounds binding to transthyretin (TTR) can be useful in amyloidosis prevention. TTR is a transporter protein that under physiological condition carries thyroxine (T₄) and retinol in plasma and in cerebrospinal fluid (CSF); it also has a neuroprotective role against Alzheimer’s disease (AD). However, TTR also is an amyloidogenic protein responsible for familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC). The TTR amyloidogenic potential is speeded up by several point mutations. One therapeutic strategy against TTR amyloidosis is the stabilisation of the native tetramer by natural compounds and small molecules. In this review, we examine the natural products that, starting from 2012 to present, have been studied as a stabiliser of TTR tetramer. In particular, we discussed the chemical and structural features which will be helpful for future drug design of new TTR stabilisers.

Early-stage aggregates of amyloid-forming proteins, specifically soluble oligomers, are implicated in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Protein aggregation is typically monitored by fluorescence using the amyloid-binding fluorophore thioflavin T (ThT). Thioflavin T interacts, however, preferentially with fibrillar amyloid structures rather than with soluble, early-stage aggregates. In contrast, the two fluorophores, aminonaphthalene 2-cyanoacrylate-spiropyran (AN-SP) and triazole-containing boron-dipyrromethene (taBODIPY), were reported to bind preferentially to early-stage aggregates of amyloidogenic proteins. The present study compares ThT with AN-SP and taBODIPY with regard to their ability to monitor early stages of aggregation of four different amyloid-forming proteins, including amyloid-β (Aβ), tau protein, amylin, and α-synuclein. The results show that the three fluorophores vary in their suitability to monitor the early aggregation of different amyloid-forming proteins. For instance, in the presence of Aβ and amylin, the fluorescence intensity of AN-SP increased at an earlier stage of aggregation than the fluorescence of ThT, albeit with only a small fluorescence increase in the case of AN-SP. In contrast, in the presence of tau and amylin, the fluorescence intensity of taBODIPY increased at an earlier stage of aggregation than the fluorescence of ThT. Finally, α-synuclein aggregation could only be monitored by ThT fluorescence; neither AN-SP nor taBODIPY showed a significant increase in fluorescence over the course of aggregation of α-synuclein. These results demonstrate the ability of AN-SP and taBODIPY to monitor the formation of early-stage aggregates from specific amyloid-forming proteins at an early stage of aggregation, although moderate increases in fluorescence intensity, relatively large uncertainties in fluorescence values, and limited solubility of both fluorophores limit their usefulness for some amyloid proteins. The capability to monitor early aggregation of some amyloid proteins, such as amylin, might accelerate the discovery of aggregation inhibitors to minimize the formation of toxic oligomeric species for potential therapeutic use.