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Amyloid-β (Aβ) and semen-derived enhancer of viral infection (SEVI) are considered as the two causative proteins for central pathogenic cause of Alzheimer’s disease (AD) and HIV/AIDS, respectively. Separately, Aβ-AD and SEVI-HIV/AIDS systems have been studied extensively both in fundamental research and in clinical trials. Despite significant differences between Aβ-AD and SEVI-HIV/AIDS systems, they share some commonalities on amyloid and antimicrobial characteristics between Aβ and SEVI, there are apparent overlaps in dysfunctional neurological symptoms between AD and HIV/AIDS. Few studies have reported a potential pathological link between Aβ-AD and SEVI-HIV/AIDS at a protein level. Here, we demonstrate the cross-seeding interactions between Aβ and SEVI proteins using in vitro and in vivo approaches. Cross-seeding of SEVI with Aβ enabled to completely prevent Aβ aggregation at sub-stoichiometric concentrations, disaggregate preformed Aβ fibrils, reduce Aβ-induced cell toxicity, and attenuate Aβ-accumulated paralysis in transgenic AD C. elegans. This work describes a potential crosstalk between AD and HIV/AIDS via the cross-seeding between Aβ and SEVI, identifies SEVI as Aβ inhibitor for possible treatment or prevention of AD, and explains the role of SEVI in the gender difference in AD.

 

Amyloid protein aggregation is associated with many neurodegenerative diseases, including amyloid‐β (Aβ)in Alzheimer disease, human islet amyloid polypeptide (hIAPP) in type II diabetes, and human calcitonin (hCT) in medullary thyroid carcinoma. Significant efforts have been made to develop different diagnostic and prevention strategies for the early detection and intervention of these disease‐causative protein aggregates. However, conventional design wisdoms are mostly limited to the molecules with either single function (amyloid imaging or amyloid prevention) or single targeting protein (Aβ, hIAPP, or hCT). Here, a rational design strategy of an amyloid‐aggregation‐induced emission (AIE)‐active molecule is demonstrated by conjugating an amyloid fragment of GNNQQNY (G7) with an AIE fluorescent molecule of triphenylvinyl benzoic acid (namely, G7‐TBA), making G7‐TBA as multiple‐target, dual‐function, amyloid probes and amyloid modulators for detecting, monitoring, and altering amyloid aggregation of three different amyloid proteins (Aβ, hIAPP, and hCT). G7‐TBA probe shows conformationally specific binding affinities to amyloid aggregates, switching from an “off” state (low fluorescence) for amyloid monomers to an “on” state (high fluorescence) for β‐structure‐rich amyloid oligomers and fibrils in aqueous solution. Further surface immobilization of TBA probes on surface plasmon resonance surfaces allows to amplify detection sensitivity and binding affinity to amyloid aggregates formed at different aggregation stages. G7‐TBA as amyloid modulator enables acceleration of amyloid fibrillization and selectively protects cells from hIAPP‐induced toxicity. The distinct amyloid detection and modulation of G7‐TBA are essentially derived from the cross‐seeding between G7 and amyloid aggregation via β‐structure interaction, which by far exceed the binding affinity between commercial ThT and amyloid aggregates. Such design concepts of amyloid‐AIE conjugates can be further explored as multiple‐function and target probes and/or modulators for biomedical applications.

 

Misfolding and aggregation of amyloid peptides are critical pathological events in numerous protein misfolding diseases (PMDs), such as Alzheimer's disease (AD), type II diabetes (T2D), and medullary thyroid carcinoma (MTC). While developing effective amyloid detectors and inhibitors to probe and prevent amyloid aggregation is a crucial diagnostic and therapeutic strategy for treating debilitating diseases, it is important to recognize that amyloid detection and amyloid prevention are two distinct strategies for developing pharmaceutical drugs. Here, we reported novel fluorescent BO21 as a versatile “dual-function, multi-target” amyloid probe and inhibitor for detecting and preventing amyloid aggregates of different sequences (Aβ, hIAPP, or hCT) and sizes (monomers, oligomers, or fibrils). As an amyloid probe, BO21 demonstrated a higher sensitivity and binding affinity to oligomeric and fibrillar amyloids compared to ThT, resulting in up to 18–39 fold fluorescence enhancements. As an amyloid inhibitor, BO21 also demonstrated its strong amyloid inhibition property by effectively preventing amyloid aggregation, disaggregating preformed amyloid fibrils, and reducing amyloid-induced cytotoxicity. The findings of this study offer a new perspective for the discovery of dual-functional amyloid probes and inhibitors, which have the potential to greatly expand the diagnostic and therapeutic treatments available for PMDs. 

Amyloids and antimicrobial peptides have traditionally been recognized as distinct families with separate biological functions and targets. However, certain amyloids and antimicrobial peptides share structural and functional characteristics that contribute to the development of neurodegenerative diseases. Specifically, the aggregation of amyloid-β (Aβ) and microbial infections are interconnected pathological factors in Alzheimer’s disease (AD). In this study, we propose and demonstrate a novel repurposing strategy for an antimicrobial peptide of protegrin-1 (PG-1), which exhibits the ability to simultaneously prevent Aβ aggregation and microbial infection both in vitro and in vivo. Through a comprehensive analysis using protein, cell, and worm assays, we uncover multiple functions of PG-1 against Aβ, including the following: (i) complete inhibition of Aβ aggregation at a low molar ratio of PG-1/Aβ = 0.25:1, (ii) disassembly of the preformed Aβ fibrils into amorphous aggregates, (iii) reduction of Aβ-induced cytotoxicity in SH-SY5Y cells and transgenic GMC101 nematodes, and (iv) preservation of original antimicrobial activity against P.A., E.coli., S.A., and S.E. strains in the presence of Aβ. Mechanistically, the dual anti-amyloid and anti-bacterial functions of PG-1 primarily arise from its strong binding to distinct Aβ seeds (KD = 1.24–1.90 μM) through conformationally similar β-sheet associations. This work introduces a promising strategy to repurpose antimicrobial peptides as amyloid inhibitors, effectively targeting multiple pathological pathways in AD. 

Since hIAPP (human islet amyloid polypeptide) aggregation and microbial infection are recognized as significant risk factors that contribute to the pathogenesis of type II diabetes (T2D), targeting these catastrophic processes simultaneously may have a greater impact on the prevention and treatment of T2D. Different from the well-studied hIAPP inhibitors, here we propose and demonstrate a repurposing strategy for an antimicrobial peptide, aurein, which can simultaneously modulate hIAPP aggregation and inhibit microbial infection. Collective data from protein, cell, and bacteria assays revealed multiple functions of aurein including (i) promotion of hIAPP aggregation at a low molar ratio of aurein:hIAPP = 0.5 : 1–2 : 1, (ii) reduction of hIAPP-induced cytotoxicity in RIN-m5F cells, and (iii) preservation of original antimicrobial activity against E. coli., S.A., and S.E. strains in the presence of hIAPP. These functions of aurein are mainly derived from its strong binding to different hIAPP seeds through conformationally similar β-sheet association. Our study provides a promising avenue for the repurposing of antimicrobial peptides (such as aurein) as amyloid modulators for blocking at least two pathological pathways in T2D. 

Neurodegenerative diseases and cancers are considered to be two families of diseases caused by completely opposite cell-death mechanisms: the former caused by premature cell death, with the latter due to the increased resistance to cell death. Growing epidemiologic evidence appear to suggest an inverse correlation between neurodegenerative diseases and cancers. However, pathological links, particularly from a protein-cell interaction perspective, between these two families of diseases remains to be proven. Here, a fundamental study investigates the effects of three amyloid proteins of Aβ (associated with AD), hIAPP (associated with T2D), and hCT (associated with MTC) on pancreatic cancer (PANC-1) cells. Collective results demonstrate a general inhibitory activity of all of three amyloid proteins on cancer cell proliferation, but inhibition efficiencies are strongly dependent on amyloid sequence (Aβ, hIAPP, hCT), concentration (IC25, IC50, IC75), and aggregation states (monomers, oligomers). Amyloid proteins exhibit two pathways against cancer cells: amyloid monomer-induced ROS production to inhibit cell growth and amyloid oligomer-induced membrane disruption to kill cells. Collectively, the results demonstrate a general inhibition function of amyloid proteins to induce cancer cell death by preventing cell proliferation, suppressing cell migration, promoting reactive oxygen species production, and disrupting cell membranes. 

Amyloid formation and microbial infection are the two common pathological causes of neurogenerative diseases, including Alzheimer's disease (AD), type II diabetes (T2D), and medullary thyroid carcinoma (MTC). While significant efforts have been made to develop different prevention strategies and preclinical hits for these diseases, conventional design strategies of amyloid inhibitors are mostly limited to either a single prevention mechanism (amyloid cascade vs. microbial infection) or a single amyloid protein (Aβ, hIAPP, or hCT), which has prevented the launch of any successful drug on the market. Here, we propose and demonstrate a new “anti-amyloid and anti-bacteria” strategy to repurpose two intestinal defensins, human α-defensin 6 (HD-6) and human β-defensin 1 (HBD-1), as multiple-target, dual-function, amyloid inhibitors. Both HD-6 and HBD-1 can cross-seed with three amyloid peptides, Aβ (associated with AD), hIAPP (associated with T2D), and hCT (associated with MTC), to prevent their aggregation towards amyloid fibrils from monomers and oligomers, rescue SH-SY5Y and RIN-m5F cells from amyloid-induced cytotoxicity, and retain their original antimicrobial activity against four common bacterial strains at sub-stoichiometric concentrations. Such sequence-independent anti-amyloid and anti-bacterial functions of intestinal defensins mainly stem from their cross-interactions with amyloid proteins through amyloid-like mimicry of β-sheet associations. In a broader view, this work provides a new out-of-the-box thinking to search and repurpose a huge source of antimicrobial peptides as amyloid inhibitors, allowing the blocking of the two interlinked pathological pathways and bidirectional communication between the central nervous system and intestines via the gut–brain axis associated with neurodegenerative diseases. 

The past decade has witnessed the growing interest and advances in aggregation-induced emission (AIE) molecules as driven by their unique fluorescence/optical properties in particular sensing applications including biomolecule sensing/detection, environmental/health monitoring, cell imaging/tracking, and disease analysis/diagnosis. In sharp contrast to conventional aggregation-caused quenching (ACQ) fluorophores, AIE molecules possess intrinsic advantages for the study of disease-related protein aggregates, but such studies are still at an infant stage with much less scientific exploration. This outlook mainly aims to provide the first systematic summary of AIE-based molecules for amyloid protein aggregates associated with neurodegenerative diseases. Despite a limited number of studies on AIE–amyloid systems, we will survey recent and important developments of AIE molecules for different amyloid protein aggregates of Aβ (associated with Alzheimer's disease), insulin (associated with type 2 diabetes), (α-syn, associated with Parkinson's disease), and HEWL (associated with familial lysozyme systemic amyloidosis) with a particular focus on the working principle and structural design of four types of AIE-based molecules. Finally, we will provide our views on current challenges and future directions in this emerging area. Our goal is to inspire more researchers and investment in this emerging but less explored subject, so as to advance our fundamental understanding and practical design/usages of AIE molecules for disease-related protein aggregates.