Currently, Alzheimer's Disease (AD) is a complex neurodegenerative condition, with limited therapeutic options. Several factors, like Amyloid ? (A?) aggregation, tau protein hyperphosphorylation, bio-metals dyshomeostasis and oxidative stress contribute to AD pathogenesis. These pathogenic processes might occur in the aqueous phase but also on neuronal membranes. Thus, investigating the connection between A? and biomembranes, becomes important for unveiling the molecular mechanism underlying A? amyloidosis as a critical event in AD pathology. In this work, the interaction of two peptides, made up with hybrid sequences from Tau protein 9-16 (EVMEDHAG) or 26-33 (QGGYTMHQ) N-terminal domain and A? (KLVFF) hydrophobic region, with full length A?40 or A?42 peptides is reported. The studied "chimera" peptides Ac-EVMEDHAGKLVFF-NH (?-KL) and Ac-QGGYTMHQKLVFF-NH (?-KL) are endowed with A? recognition and metal ion interaction capabilities provided by the tau or A? sequences, respectively. These peptides were characterized in previous study along with their metal dependent interaction and amyloidogenesis, either in the presence or absence of metal ion and artificial membranes made up with Total Lipid Brain Extract (TLBE) components, (Sciacca et al., 2020). In the present paper, the ability of the two peptides to inhibit A? aggregation is studied using composite experimental conditions including aqueous solution, the presence of metal ions (Cu or Zn), the presence of lipid vesicles mimicking neuronal membranes as well as the co-presence of metals and TLBE artificial membranes. We used Thioflavine-T (ThT) fluorescence or MALDI-TOF spectrometry analysis of A? limited proteolysis to respectively monitor the A? aggregation kinetic or validation of the A? interacting regions. We demonstrate that ?-KL and ?-KL peptides differently affect A? aggregation kinetics, with the tau sequence playing a crucial role. The results are discussed in terms of chimera's peptides hydrophobicity and electrostatic driven interactions at the aqueous/membrane interface.
Tau/A? chimera peptides: A Thioflavin-T and MALDI-TOF study of A? amyloidosis in the presence of Cu(II) or Zn(II) ions and total lipid brain extract (TLBE) vesicles
Di Natale G;Milardi D;Pappalardo G
2021
Abstract
Currently, Alzheimer's Disease (AD) is a complex neurodegenerative condition, with limited therapeutic options. Several factors, like Amyloid ? (A?) aggregation, tau protein hyperphosphorylation, bio-metals dyshomeostasis and oxidative stress contribute to AD pathogenesis. These pathogenic processes might occur in the aqueous phase but also on neuronal membranes. Thus, investigating the connection between A? and biomembranes, becomes important for unveiling the molecular mechanism underlying A? amyloidosis as a critical event in AD pathology. In this work, the interaction of two peptides, made up with hybrid sequences from Tau protein 9-16 (EVMEDHAG) or 26-33 (QGGYTMHQ) N-terminal domain and A? (KLVFF) hydrophobic region, with full length A?40 or A?42 peptides is reported. The studied "chimera" peptides Ac-EVMEDHAGKLVFF-NH (?-KL) and Ac-QGGYTMHQKLVFF-NH (?-KL) are endowed with A? recognition and metal ion interaction capabilities provided by the tau or A? sequences, respectively. These peptides were characterized in previous study along with their metal dependent interaction and amyloidogenesis, either in the presence or absence of metal ion and artificial membranes made up with Total Lipid Brain Extract (TLBE) components, (Sciacca et al., 2020). In the present paper, the ability of the two peptides to inhibit A? aggregation is studied using composite experimental conditions including aqueous solution, the presence of metal ions (Cu or Zn), the presence of lipid vesicles mimicking neuronal membranes as well as the co-presence of metals and TLBE artificial membranes. We used Thioflavine-T (ThT) fluorescence or MALDI-TOF spectrometry analysis of A? limited proteolysis to respectively monitor the A? aggregation kinetic or validation of the A? interacting regions. We demonstrate that ?-KL and ?-KL peptides differently affect A? aggregation kinetics, with the tau sequence playing a crucial role. The results are discussed in terms of chimera's peptides hydrophobicity and electrostatic driven interactions at the aqueous/membrane interface.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
