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O3‐02–04: Increased levels of CSF Aβ oligomers in Alzheimer's disease: Combination of techniques allows indirect estimates
Author(s) -
Englund Hillevi,
Sehlin Dag,
Gunnarsson Malin Degerman,
Lord Anna,
Brundin RoseMarie,
Ingelsson Martin,
Kilander Lena,
Nilsson Lars N.G.,
Pettersson Frida Ekholm,
Lannfelt Lars
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.417
Subject(s) - oligomer , pathogenesis , in vivo , genetically modified mouse , quotient , western blot , in vitro , microbiology and biotechnology , chemistry , transgene , pathology , medicine , biochemistry , biology , genetics , gene , mathematics , organic chemistry , pure mathematics
Background: Soluble oligomeric amyloid(A ) is expected to be involved in the pathogenesis of Alzheimer’s disease (AD) as they mediate neurotoxicity both in vitro and in vivo. Oligomeric A in CSF have been suggested as a possible marker of AD and is thought to reflect the ongoing neurodegenerative process. Among the several oligomeric species described, the Arctic mutation (A E22G) provides clinical support for A protofibrils as a pathogenic species. The objective of this study was to evaluate the oligomer quotient as a diagnostic marker in CSF using samples from patients with different dementia diagnoses. Methods: TBS-soluble extracts from human and transgenic mouse brains and human CSF were analyzed with Western blot and C-terminal-specific ELISAs. Brain extracts were also analyzed with the protofibril specific mAb158 ELISA (Englund et al, 2007). Results: The oligomer quotient was determined with respect to total A content and C-terminal A signal, and based on a combination of well established denaturing and non-denaturing methods. For evaluation of this measure, transgenic AD mouse models were analyzed for both their oligomer quotient and their protofibril levels, specifically measured by the mAb158 sandwich ELISA. tg-ArcSwe mice (Lord et al, 2006) displayed A protofibrils in brain before onset of plaque pathology and the oligomer quotient agreed well with protofibril content. These results are now being confirmed in human brain samples. The oligomer quotient in 43 CSF samples from AD, MCI and FTD patients as well as healthy controls was determined and the quotient was highest for AD patients. It also distinguished AD from FTD and healthy controls (p 0.05). These results indicate that A oligomers are present in CSF and of possible diagnostic value. Additionally, results from this study imply that the reduced levels of A 42 in CSF found in AD could, at least partially be due to oligomerization of A . Conclusions: The oligomer quotient is an indirect measurement of oligomeric A in CSF and in tg-ArcSwe mouse brain. The quotient correlates with A protofibril levels, and offers opportunities to expand the panel of early markers for AD.