MORPHOLOGY AND TOXICITY OF A-BETA-(1-42) DIMER DERIVED FROM NEURITIC AND VASCULAR AMYLOID DEPOSITS OF ALZHEIMERS-DISEASE

In the course of analyzing the chemical composition of Alzheimer's dis ease neuritic and vascular amyloid, we have purified stable dimeric an d trimeric components of A beta peptides, These peptides (molecular ma ss 9.0 and 13.5 kDa) were separated by size exclusion chromatography i n the presence of 80% formic acid or 5 M. guanidine thiocyanate, pH 7. 4, The average ratio of monomers, dimers, and trimers was 55:30:15, re spectively, Similar structures were produced over time upon incubation of synthetic A beta-(1-42) at pH 7.4, The stability of these oligomer ic forms was also demonstrated by Western blot and mass spectrometry, Atomic force microscopy and electron microscopy rotary shadowing revea led that the monomers polymerized into 8-10-nm filaments, whereas the dimers generated prolate ellipsoids measuring 3-4 nm in diameter, The pathogenic effects of the dimeric A beta-(1-40/42) were tested in cult ures of rat hippocampal neuron glia cells. Only in the presence of mic roglia did the dimer elicit neuronal killing. It is possible that thes e potentially pathogenic A beta-(1-40/42) dimers and trimers from Alzh eimer's disease amyloid represent the soluble oligomers of A beta rece ntly described in Alzheimer's disease brains (Kuo, Y.-M., Emmerling, M . R., Vigo-Pelfrey, C., Kasunic, T. C., Kirkpatrick, J. B., Murdoch, G . H,, Ball, M. J., and Roher, A. E. (1996) J. Biol, Chem., 271, 4077-4 081).