Amyloid toxicity is independent of polypeptide sequence, length and chirality.
By using an amyloid sequence pattern, here we have identified putative six-residue amyloidogenic stretches in several relevant amyloid proteins. Hexapeptides synthesized on the bases of the sequence stretches matching the pattern have been shown to form amyloid fibrils in vitro. As larger pathological peptides such as A beta(1-42) do, these short amyloid peptides form heterogeneous mixtures of small aggregates that induce cell death in PC12 cells and primary hippocampal neurons. Toxic mixtures of small aggregates from these hexapeptides bind to cell membranes and can be further internalized, as also observed for natural amyloid proteins. In neurons, toxic aggregates obtained from the full length A beta(1-42) amyloid peptide or their amyloid stretch A beta(16-21) peptide preferentially localize in synapses, leading to the re-organization of the underlying actin cytoskeleton. This process does not involve stereospecific interactions between membrane and toxic species as D-sequences are as toxic as L ones, suggesting that is not receptor mediated. Based on these results, we propose here that regardless of polypeptide sequence, length and amino acid chirality, amyloid prefibrillar aggregates exert their cytotoxic effect through a common cell death mechanism related to a particular quaternary structure. The degree of toxicity of these species seems to depend, however, on cell membrane composition.
Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
M Teresa
MT
Pastor
Nico
N
Kümmerer
Vanessa
V
Schubert
Alexandra
A
Esteras-Chopo
Carlos G
CG
Dotti
Manuela
M
López de la Paz
Luis
L
Serrano
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity* / Q000648:ultrastructure; D000818:Animals; D052160:Benzothiazoles; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002942:Circular Dichroism; D055316:Cystatin C; D015891:Cystatins / Q000737:chemistry; D005562:Formazans / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007700:Kinetics; D013058:Mass Spectrometry; D008970:Molecular Weight; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D010455:Peptides / Q000737:chemistry / Q000633:toxicity*; D011328:Prions / Q000737:chemistry / Q000648:ultrastructure; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D051381:Rats; D013010:Sonication; D013569:Synapses / Q000378:metabolism; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; C525030:CST3 protein, human; C525032:Cst3 protein, rat; D055316:Cystatin C; D015891:Cystatins; D005562:Formazans; D010446:Peptide Fragments; D010455:Peptides; D011328:Prions; D013778:Tetrazolium Salts; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C079782:MTT formazan; C009462:thioflavin T