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O2‐01‐07: Baseline cerebrospinal fluid markers in healthy middle‐aged adults predict brain health at three‐year follow‐up
Author(s) -
Bendlin Barbara,
Sodhi Aparna,
Willette Auriel,
Johnson Sterling,
Ries Michele,
Hawley Amy,
Alexander Andrew,
Puglielli Luigi,
Asthana Sanjay,
Zetterberg Henrik,
Blennow Kaj,
Sager Mark
Publication year - 2011
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.2011.09.012
Subject(s) - white matter , diffusion mri , fractional anisotropy , medicine , cerebrospinal fluid , biomarker , oncology , pathology , magnetic resonance imaging , biology , radiology , biochemistry
reflect specific cleavage sites in proteins and, due to their smaller size, will pass the BBB. Importantly, these smaller protein fragments include more information than their intact counterparts, namely that the proteins are degraded by specific enzymes, a cardinal feature of the brain damage in AD. Methods: Tau was cleaved with BACE1, ADAM10 and caspase 3, and fragments were identified by Mass spectrometry. 10 different fragments of tau was selected for monoclonal antibody development, and one assay measuring tau degradation mediated by the protease ADAM10 using an ELISA assay (NB191) was developed. 33 paired CSF and serum samples from patients with severe ADwere investigated. Brains fromwild-type (wt) and Tg4510 transgenic mice known to develop some aspects of Alzheimer’s disease were extracted. Results: The NB191 antibody recognized the cleavage site generated by ADAM10 with an IC50 of 12.5ng/mL, but not an elongated sequence with one more amino acid (see figure). Technically robust and measurable levels of the tau neoepitope in human Alzheimer’s disease patient sera and CSF samples with averages of 21ng/ml and 2ng/ mL respectively were obtained. Finally, we compared the levels of NB191 in CSF to the levels in serum and found a correlation of R 1⁄4 0.45, borderline significant. Brain extracts from Tg4510 mice had 10-fold elevated levels of the tau neoepitope when compared to wildtype controls (p <0.001). Conclusions: In summary, we have developed a serological tau neoepitope biomarker assay that, as it crosses the BBB, may be useful for assessment of neurodegeneration in Alzheimer’s disease patients.