Oligomerization partially explains the lowering of Abeta42 in Alzheimer's disease cerebrospinal fluid.
OBJECTIVE
The lowering of natively analyzed Abeta42 in cerebrospinal fluid (CSF) is used as a diagnostic tool in Alzheimer's disease (AD). The presence of Abeta oligomers can interfere with such analyses causing underestimation of Abeta levels due to epitope masking. The aim was to investigate if the lowering of CSF Abeta42 seen in AD is caused by oligomerization.


METHODS
Abeta42 was analyzed under both denaturing and non-denaturing conditions. An Abeta42 oligomer ratio was calculated from these quantifications. The presence of oligomers leads to Abeta42 epitope masking during non-denaturing assays, resulting in a higher ratio.


RESULTS
The Abeta42 oligomer ratio was used for the assessment of oligomerized Abeta in human CSF, after being evaluated in transgenic mouse brain homogenates. AD and mild cognitive impairment (MCI) samples displayed the expected decrease in natively measured Abeta42 compared to healthy controls and frontotemporal dementia, but not when analyzing under denaturing conditions. Accordingly, AD and MCI CSF had a higher Abeta42 oligomer ratio in CSF.


CONCLUSIONS
Combining denaturing and non-denaturing quantifications of Abeta42 into an oligomer ratio enables the assessment of Abeta oligomers in biological samples. The increased Abeta42 oligomer ratio for AD and MCI indicates the presence of oligomers in CSF and that the lowering of natively measured Abeta42 is caused by oligomerization.
Englund
Hillevi
H
Department of Public Health and Caring Sciences/Molecular Geriatrics, Rudbeck Laboratory Uppsala University, Uppsala, Sweden.
Degerman Gunnarsson
Malin
M
Brundin
Rose Marie
RM
Hedlund
Marie
M
Kilander
Lena
L
Lannfelt
Lars
L
Pettersson
Frida Ekholm
FE
D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid*; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D003072:Cognition Disorders / Q000134:cerebrospinal fluid; D003704:Dementia / Q000134:cerebrospinal fluid; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000134:cerebrospinal fluid* / Q000378:metabolism*; D010766:Phosphorylation; D055503:Protein Multimerization; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000378:metabolism
D000682:Amyloid; D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins