WATER-SOLUBLE A-BETA (N-40, N-42) OLIGOMERS IN NORMAL AND ALZHEIMER-DISEASE BRAINS

Ultracentrifugation and graded molecular sieving, as well as a sensiti ve sandwich enzyme-linked immunosorbent assay were used to isolate and quantitate the amounts of water-soluble oligomers of beta amyloid (A beta) peptides N-40 and N-42 in cerebral cortex of normal and Alzheime r disease (AD) brains. AD brains contained 6-fold more water-soluble A beta (wsA beta) than control brains. The majority of water-soluble pe ptides in most AD cases was A beta N-42, representing 12 times the amo unt found in control brains, The wsA beta was present in the form of m onomers and oligomers ranging from less than 10 kDa to greater than 10 0 kDa. The amount of wsA beta N-42 in AD brains is about 50 times grea ter than the level of soluble A beta N-42 found in the CSF of AD patie nts. This disparity may be due to the rapid association of wsA beta N- 42 into fibrillar deposits and/or to the integrity of the anatomical b arriers which separate the two extracellular spaces. In this paper, me consider soluble any form of A beta which has not yet polymerized int o its insoluble, filamentous form. This includes both the newly synthe sized forms of A beta and those peptides which may be loosely attached to insoluble filaments but which can, nevertheless, still be consider ed soluble. It has been previously shown that, once it has aggregated into its filamentous form, the A beta peptides are resistant to disagg regation and degradation by a number of denaturing agents and aqueous buffers containing proteolytic enzymes. Therefore, it is likely that t he water-soluble A beta peptides we quantified are precursors to its i nsoluble, filamentous form. Consequently, reducing the levels of solub le A beta in AD brains could have profound effects on AD pathophysiolo gy.