Oligomerization of beta-amyloid of the Alzheimer's and the Dutch-cerebral-haemorrhage types.
A novel ELISA has been developed which detects oligomerization of beta-amyloid (A beta). Oligomerization, fibrillization and neurotoxicity of native A beta associated with Alzheimer's disease (AD) type has been compared with E22Q A beta (amyloid beta-protein containing residues 1--40 with the native Glu at residue 22 changed to Gln) implicated in Dutch cerebral haemorrhage disease. Solutions of A beta rapidly yield soluble oligomers in a concentration-dependent manner, which are detected by the ELISA, and by size-exclusion gel chromatography. Conformational changes from disordered to beta-sheet occur more slowly than oligomerization, and fibrils are produced after prolonged incubation. The E22Q A beta oligomerizes, changes conformation and fibrillizes more rapidly than the native form and produces shorter stubbier fibrils. Aged fibrillar preparations of E22Q A beta are more potent than aged fibrils of native A beta in inducing apoptotic changes and toxic responses in human neuroblastoma cell lines, whereas low-molecular-mass oligomers in briefly incubated solutions are much less potent. The differences in the rates of oligomerization of the two A beta forms, their conformational behaviour over a range of pH values, and NMR data reported elsewhere, are consistent with a molecular model of oligomerization in which strands of A beta monomers initially overcome charge repulsion to form dimers in parallel beta-sheet arrangement, stabilized by intramolecular hydrophobic interactions, with amino acids of adjacent chains in register.
Sian
A K
AK
Department of Surgery, St. George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK.
Frears
E R
ER
El-Agnaf
O M
OM
Patel
B P
BP
Manca
M F
MF
Siligardi
G
G
Hussain
R
R
Austen
B M
BM
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D017209:Apoptosis; D019921:Biotinylation; D002543:Cerebral Hemorrhage / Q000378:metabolism*; D002850:Chromatography, Gel; D002942:Circular Dichroism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008854:Microscopy, Electron; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D013997:Time Factors; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides