A critical concentration of N-terminal pyroglutamylated amyloid beta drives the misfolding of Ab1-42 into more toxic aggregates.
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.
Institute for Macromolecular Studies, National Research Council, 16149 Genova, Italy; Section of Pharmacology, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genova, 16132 Genova, Italy.
Denise
D
Galante
Ecole Polytechnique Federale de Lausanne (EPLF), 1015 Lausanne, Switzerland; Department of Chemistry, University of Cambridge, CB21EW, United Kingdom.
Francesco Simone
FS
Ruggeri
Ecole Polytechnique Federale de Lausanne (EPLF), 1015 Lausanne, Switzerland.
Giovanni
G
Dietler
Department of Physics, University of Genova, 16100 Genova, Italy.
Francesca
F
Pellistri
Department of Physics, University of Genova, 16100 Genova, Italy.
Elena
E
Gatta
Section of Pharmacology, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genova, 16132 Genova, Italy.
Alessandro
A
Corsaro
Section of Pharmacology, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genova, 16132 Genova, Italy.
Tullio
T
Florio
Institute for Macromolecular Studies, National Research Council, 16149 Genova, Italy.
Angelo
A
Perico
Institute for Macromolecular Studies, National Research Council, 16149 Genova, Italy. Electronic address: cristina.darrigo@ge.ismac.cnr.it.
Cristina
C
D'Arrigo
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity*; D066329:Protein Aggregates; D000072757:Protein Conformation, beta-Strand; D017510:Protein Folding; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D002118:Calcium; D011761:Pyrrolidonecarboxylic Acid
Alzheimer’s disease; Calcium homeostasis; Conformational structure; Morphology; Toxicity; β amyloids