Soluble oligomers from a non-disease related protein mimic Abeta-induced tau hyperphosphorylation and neurodegeneration.
Protein aggregation and amyloid accumulation in different tissues are associated with cellular dysfunction and toxicity in important human pathologies, including Alzheimer's disease and various forms of systemic amyloidosis. Soluble oligomers formed at the early stages of protein aggregation have been increasingly recognized as the main toxic species in amyloid diseases. To gain insight into the mechanisms of toxicity instigated by soluble protein oligomers, we have investigated the aggregation of hen egg white lysozyme (HEWL), a normally harmless protein. HEWL initially aggregates into beta-sheet rich, roughly spherical oligomers which appear to convert with time into protofibrils and mature amyloid fibrils. HEWL oligomers are potently neurotoxic to rat cortical neurons in culture, while mature amyloid fibrils are little or non-toxic. Interestingly, when added to cortical neuronal cultures HEWL oligomers induce tau hyperphosphorylation at epitopes that are characteristically phosphorylated in neurons exposed to soluble oligomers of the amyloid-beta peptide. Furthermore, injection of HEWL oligomers in the cerebral cortices of adult rats induces extensive neurodegeneration in different brain areas. These results show that soluble oligomers from a non-disease related protein can mimic specific neuronal pathologies thought to be induced by soluble amyloid-beta peptide oligomers in Alzheimer's disease and support the notion that amyloid oligomers from different proteins may share common structural determinants that would explain their generic cytotoxicities.
Vieira
Marcelo N N
MN
Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Forny-Germano
Letícia
L
Saraiva
Leonardo M
LM
Sebollela
Adriano
A
Martinez
Ana M Blanco
AM
Houzel
Jean-Christophe
JC
De Felice
Fernanda G
FG
Ferreira
Sérgio T
ST
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D052160:Benzothiazoles; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002645:Chickens; D002850:Chromatography, Gel; D002942:Circular Dichroism; D004591:Electrophoresis, Polyacrylamide Gel; D000939:Epitopes; D005260:Female; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D008854:Microscopy, Electron; D009113:Muramidase / Q000737:chemistry* / Q000633:toxicity*; D009391:Nephelometry and Turbidimetry; D009410:Nerve Degeneration / Q000139:chemically induced*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013844:Thiazoles; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D000939:Epitopes; D005456:Fluorescent Dyes; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T; D009113:Muramidase