Immunological memory to hyperphosphorylated tau in asymptomatic individuals
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Author
Pascual, Gabriel
Wadia, Jehangir S.
Zhu, Xueyong
Keogh, Elissa
Kükrer, Başak
van Ameijde, Jeroen
Inganäs, Hanna
Siregar, Berdien
Perdok, Gerrard
Diefenbach, Otto
Nahar, Tariq
Sprengers, Imke
Koldijk, Martin H.
der Linden, Els C. Brinkman-van
Peferoen, Laura A.
Zhang, Heng
Yu, Wenli
Li, Xinyi
Wagner, Michelle
Moreno, Veronica
Kim, Julie
Costa, Martha
West, Kiana
Fulton, Zara
Chammas, Lucy
Luckashenak, Nancy
Fletcher, Lauren
Holland, Trevin
Arnold, Carrie
Anthony Williamson, R.
Hoozemans, Jeroen J.
Apetri, Adrian
Bard, Frederique
Wilson, Ian A.
Koudstaal, Wouter
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1007/s00401-017-1705-yMetadata
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Pascual, G., J. S. Wadia, X. Zhu, E. Keogh, B. Kükrer, J. van Ameijde, H. Inganäs, et al. 2017. “Immunological memory to hyperphosphorylated tau in asymptomatic individuals.” Acta Neuropathologica 133 (5): 767-783. doi:10.1007/s00401-017-1705-y. http://dx.doi.org/10.1007/s00401-017-1705-y.Abstract
Several reports have described the presence of antibodies against Alzheimer’s disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG+ memory B cells from asymptomatic blood donors for reactivity to a panel of phosphorylated tau peptides using a single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs. In total, 52 somatically mutated tau-binding antibodies were identified, corresponding to 35 unique clonal families. Forty-one of these antibodies recognize epitopes in the proline-rich and C-terminal domains, and binding of 26 of these antibodies is strictly phosphorylation dependent. Thirteen antibodies showed inhibitory activity in a P301S lysate seeded in vitro tau aggregation assay. Two such antibodies, CBTAU-7.1 and CBTAU-22.1, which bind to the proline-rich and C-terminal regions of tau, respectively, were characterized in more detail. CBTAU-7.1 recognizes an epitope that is similar to that of murine anti-PHF antibody AT8, but has different phospho requirements. Both CBTAU-7.1 and CBTAU-22.1 detect pathological tau deposits in post-mortem brain tissue. CBTAU-7.1 reveals a similar IHC distribution pattern as AT8, immunostaining (pre)tangles, threads, and neuritic plaques. CBTAU-22.1 shows selective detection of neurofibrillary changes by IHC. Taken together, these results suggest the presence of an ongoing antigen-driven immune response against tau in healthy individuals. The wide range of specificities to tau suggests that the human immune repertoire may contain antibodies that can serve as biomarkers or be exploited for therapy. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1705-y) contains supplementary material, which is available to authorized users.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390017/pdf/Terms of Use
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