Water-soluble Abeta (N-40, N-42) oligomers in normal and Alzheimer disease brains.
Ultracentrifugation and graded molecular sieving, as well as a sensitive sandwich enzyme-linked immunosorbent assay were used to isolate and quantitate the amounts of water-soluble oligomers of beta amyloid (Abeta) peptides N-40 and N-42 in cerebral cortex of normal and Alzheimer disease (AD) brains. AD brains contained 6-fold more water-soluble Abeta (wsAbeta) than control brains. The majority of water-soluble peptides in most AD cases was A beta N-42, representing 12 times the amount found in control brains. The wsAbeta was present in the form of monomers and oligomers ranging from less than 10 kDa to greater than 100 kDa. The amount of wsAbeta N-42 in AD brains is about 50 times greater than the level of soluble Abeta N-42 found in the CSF of AD patients. This disparity may be due to the rapid association of wsAbeta N-42 into fibrillar deposits and/or to the integrity of the anatomical barriers which separate the two extracellular spaces. In this paper, we consider soluble any form of Abeta which has not yet polymerized into its insoluble, filamentous form. This includes both the newly synthesized forms of Abeta and those peptides which may be loosely attached to insoluble filaments but which can, nevertheless, still be considered soluble. It has been previously shown that, once it has aggregated into its filamentous form, the Abeta peptides are resistant to disaggregation and degradation by a number of denaturing agents and aqueous buffers containing proteolytic enzymes. Therefore, it is likely that the water-soluble Abeta peptides we quantified are precursors to its insoluble, filamentous form. Consequently, reducing the levels of soluble Abeta in AD brains could have profound effects on AD pathophysiology.
Kuo
Y M
YM
Sun Health Research Institute, Sun City, Arizona 85372, USA.
Emmerling
M R
MR
Vigo-Pelfrey
C
C
Kasunic
T C
TC
Kirkpatrick
J B
JB
Murdoch
G H
GH
Ball
M J
MJ
Roher
A E
AE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000737:chemistry* / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003956:Dialysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D046911:Macromolecular Substances; D008297:Male; D008970:Molecular Weight; D012995:Solubility; D014461:Ultracentrifugation; D014462:Ultrafiltration
D016229:Amyloid beta-Peptides; D046911:Macromolecular Substances