Amyloidogenic amyloid-β-peptide variants induce microbial agglutination and exert antimicrobial activity

Abstract

Amyloid-β (Aβ) peptides are the main components of the plaques found in the brains of patients with Alzheimer’s disease. However, Aβ peptides are also detectable in secretory compartments and peripheral blood contains a complex mixture of more than 40 different modified and/or N- and C-terminally truncated Aβ peptides. Recently, anti-infective properties of Aβ peptides have been reported. Here, we investigated the interaction of Aβ peptides of different lengths with various bacterial strains and the yeast Candida albicans. The amyloidogenic peptides Aβ1-42, Aβ2-42, and Aβ3p-42 but not the non-amyloidogenic peptides Aβ1-40 and Aβ2-40 bound to microbial surfaces. As observed by immunocytochemistry, scanning electron microscopy and Gram staining, treatment of several bacterial strains and Candida albicans with Aβ peptide variants ending at position 42 (Aβx-42) caused the formation of large agglutinates. These aggregates were not detected after incubation with Aβx-40. Furthermore, Aβx-42 exerted an antimicrobial activity on all tested pathogens, killing up to 80% of microorganisms within 6 h. Aβ1-40 only had a moderate antimicrobial activity against C. albicans. Agglutination of Aβ1-42 was accelerated in the presence of microorganisms. These data demonstrate that the amyloidogenic Aβx-42 variants have antimicrobial activity and may therefore act as antimicrobial peptides in the immune system.

Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism

“…Indeed, amyloidogenic aggregates are implicated in a broad range of protein misfolding diseases, such as Parkinson's disease, Huntington's disease, and Alzheimer's disease (AD). Moreover, amyloidogenic amyloid β-peptide variants have been shown to exert antimicrobial activity (27,28). Furthermore, peptides derived from the disulfideconstrained loop region of human β-amyloid precursor protein and the N terminus of human prion protein are antimicrobial (29,30).…”

What Is the “Relevant” Amyloid β42 Concentration?

“…This prompts a note of caution with regard to therapeutic approaches that act by solubilizing Aβ fibrils and plaques, as these approaches might result in the undesirable release of toxic entities. It is worth noting that Aβ42 is also bactericidal and is capable of killing 80 % of various microorganisms within 6 h of application at 50 μg mL −1 (11 μ m ) . Whether Aβ42 has truly evolved to be part of the host immune system remains the subject of active research…”

Amyloid aggregation and membrane activity of the antimicrobial peptide uperin 3.5

“…A beguiling hypothesis is that amyloidogenic peptides are antimicrobial, host‐defense peptides . In accordance with this, amyloidogenic peptides and antimicrobial peptides (AMPs) share the ability to bind to/within a cell membrane inducing a similar permeation (barrel‐stave or toroidal pores) or disruption (carpet or detergent effect) of the membrane, while doing so via potentially different mechanisms .…”