TY - JOUR
T1 - A critical concentration of N-terminal pyroglutamylated amyloid beta drives the misfolding of Ab1-42 into more toxic aggregates
AU - Galante, Denise
AU - Ruggeri, Francesco Simone
AU - Dietler, Giovanni
AU - Pellistri, Francesca
AU - Gatta, Elena
AU - Corsaro, Alessandro
AU - Florio, Tullio
AU - Perico, Angelo
AU - D'Arrigo, Cristina
PY - 2016/10/1
Y1 - 2016/10/1
N2 - A wide consensus based on robust experimental evidence indicates pyroglutamylated amyloid-β isoform (AβpE3-42) as one of the most neurotoxic peptides involved in the onset of Alzheimer's disease. Furthermore, AβpE3-42 co-oligomerized with excess of Aβ1-42, produces oligomers and aggregates that are structurally distinct and far more cytotoxic than those made from Aβ1-42 alone. Here, we investigate quantitatively the influence of AβpE3-42 on biophysical properties and biological activity of Aβ1-42. We tested different ratios of AβpE3-42/Aβ1-42 mixtures finding a correlation between the biological activity and the structural conformation and morphology of the analyzed mixtures. We find that a mixture containing 5% AβpE3-42, induces the highest disruption of intracellular calcium homeostasis and the highest neuronal toxicity. These data correlate to an high content of relaxed antiparallel β-sheet structure and the coexistence of a population of big spheroidal aggregates together with short fibrils. Our experiments provide also evidence that AβpE3-42 causes template-induced misfolding of Aβ1-42 at ratios below 33%. This means that there exists a critical concentration required to have seeding on Aβ1-42 aggregation, above this threshold, the seed effect is not possible anymore and AβpE3-42 controls the total aggregation kinetics.
AB - A wide consensus based on robust experimental evidence indicates pyroglutamylated amyloid-β isoform (AβpE3-42) as one of the most neurotoxic peptides involved in the onset of Alzheimer's disease. Furthermore, AβpE3-42 co-oligomerized with excess of Aβ1-42, produces oligomers and aggregates that are structurally distinct and far more cytotoxic than those made from Aβ1-42 alone. Here, we investigate quantitatively the influence of AβpE3-42 on biophysical properties and biological activity of Aβ1-42. We tested different ratios of AβpE3-42/Aβ1-42 mixtures finding a correlation between the biological activity and the structural conformation and morphology of the analyzed mixtures. We find that a mixture containing 5% AβpE3-42, induces the highest disruption of intracellular calcium homeostasis and the highest neuronal toxicity. These data correlate to an high content of relaxed antiparallel β-sheet structure and the coexistence of a population of big spheroidal aggregates together with short fibrils. Our experiments provide also evidence that AβpE3-42 causes template-induced misfolding of Aβ1-42 at ratios below 33%. This means that there exists a critical concentration required to have seeding on Aβ1-42 aggregation, above this threshold, the seed effect is not possible anymore and AβpE3-42 controls the total aggregation kinetics.
KW - Alzheimer's disease
KW - Calcium homeostasis
KW - Conformational structure
KW - Morphology
KW - Toxicity
KW - β amyloids
U2 - 10.1016/j.biocel.2016.08.037
DO - 10.1016/j.biocel.2016.08.037
M3 - Article
C2 - 27592450
AN - SCOPUS:84984873363
SN - 1357-2725
VL - 79
SP - 261
EP - 270
JO - International Journal of Biochemistry and Cell Biology
JF - International Journal of Biochemistry and Cell Biology
ER -