Cellular Polyamines Promote Amyloid-Beta (Aβ) Peptide Fibrillation and Modulate the Aggregation Pathways

Abstract

The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer's disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (Aβ) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric Aβ(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 μM spermine (normal intracellular concentration is ~1 mM) significantly decreased the lag and transition times of the aggregation process. Spermidine and putrescine additions yielded similar but weaker effects. CD measurements demonstrated that the three polyamines induce different aggregation pathways, involving different forms of induced secondary structure. This is supported by AFM images showing that the three polyamines induce Aβ(1-40) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of Aβ peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer's disease.

Remaining Mysteries of Molecular Biology: The Role of Polyamines in the Cell

“…(associated with PD [232]), while aggregates of amyloid-β (associated with AD) were potentiated by Put, Spd and Spm [233]. In addition, Spm enhanced α-syn toxicity in a PD yeast model [234].…”

Putrescine as indicator of manganese neurotoxicity: Dose-response study in human SH-SY5Y cells

“…These data suggest that polyamines play a role in major neurological and age-related disorders (Antony et al, 2003; Luo et al, 2013). Polyamines also impact functions of multiple ion channels (Agostinelli, 2016; Ahern et al, 2006; Williams, 1997), raising the possibility that Mn-induced changes in putrescine and related polyamines could impact neurologic disorders without causing cell death.…”

“…Cationic polyamines accelerate aggregation and fibrillation of alpha synuclein in Parkinson’s disease (Antony et al, 2003) and accelerated aggregation of amyloid-beta (Aβ) peptide in Alzheimer’s disease potentially via electrostatic interaction between N-terminal regions of polyamine amyloid-beta (Aβ) peptide possessing negative charge and the positively charged polyamines ()(Luo et al, 2013). These data suggest that polyamines play a role in major neurological and age-related disorders (Antony et al, 2003; Luo et al, 2013).…”

Interaction of polymers with amyloidogenic peptides

“…Spermidine and putrescine addition induced similar but weaker effects. Different polyamines thus induce different aggregation pathways, in particular various secondary structures and hence morphologies . The different aggregation pathways are confirmed by AFM imaging, which revealed different aggregation products.…”