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-amyl oid (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 concentra tion-dependent manner, which are detected by the ELISA, and by size-exclusi on gel chromatography. Conformational changes from disordered to beta-sheet occur more slowly than oligomerization, and fibrils are produced after pro longed incubation. The E22Q A beta oligomerizes, changes conformation and f ibrillizes more rapidly than the native form and produces shorter stubbier fibrils, Aged fibrillar preparations of E22Q A beta are more potent than ag ed fibrils of native A beta in inducing apoptotic changes and toxic respons es 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 beh aviour over a range of pH values, and NMR data reported elsewhere, are cons istent with a molecular model of oligomerization in which strands of A beta monomers initially overcome charge repulsion to form dimers in parallel be ta-sheet arrangement, stabilized by intramolecular hydrophobic interactions , with amino acids of adjacent chains in register.