Size-dependent neurotoxicity of beta-amyloid oligomers.
The link between the size of soluble amyloid beta (Abeta) oligomers and their toxicity to rat cerebellar granule cells (CGC) was investigated. Variation in conditions during in vitro oligomerization of Abeta(1-42) resulted in peptide assemblies with different particle size as measured by atomic force microscopy and confirmed by dynamic light scattering and fluorescence correlation spectroscopy. Small oligomers of Abeta(1-42) with a mean particle z-height of 1-2 nm exhibited propensity to bind to phospholipid vesicles and they were the most toxic species that induced rapid neuronal necrosis at submicromolar concentrations whereas the bigger aggregates (z-height above 4-5 nm) did not bind vesicles and did not cause detectable neuronal death. A similar neurotoxic pattern was also observed in primary cultures of cortex neurons whereas Abeta(1-42) oligomers, monomers and fibrils were non-toxic to glial cells in CGC cultures or macrophage J774 cells. However, both oligomeric forms of Abeta(1-42) induced reduction of neuronal cell densities in the CGC cultures.
Cizas
Paulius
P
Institute for Biomedical Research, Kaunas University of Medicine, Kaunas, Lithuania; Department of Biochemistry, Kaunas University of Medicine, Kaunas, Lithuania.
Budvytyte
Rima
R
Morkuniene
Ramune
R
Moldovan
Radu
R
Broccio
Matteo
M
Lösche
Mathias
M
Niaura
Gediminas
G
Valincius
Gintaras
G
Borutaite
Vilmante
V
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D008970:Molecular Weight; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)