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2017 ; 133
(5
): 767-783
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Immunological memory to hyperphosphorylated tau in asymptomatic individuals
#MMPMID28341999
Pascual G
; Wadia JS
; Zhu X
; Keogh E
; Kükrer B
; van Ameijde J
; Inganäs H
; Siregar B
; Perdok G
; Diefenbach O
; Nahar T
; Sprengers I
; Koldijk MH
; der Linden EC
; Peferoen LA
; Zhang H
; Yu W
; Li X
; Wagner M
; Moreno V
; Kim J
; Costa M
; West K
; Fulton Z
; Chammas L
; Luckashenak N
; Fletcher L
; Holland T
; Arnold C
; Anthony Williamson R
; Hoozemans JJ
; Apetri A
; Bard F
; Wilson IA
; Koudstaal W
; Goudsmit J
Acta Neuropathol
2017[May]; 133
(5
): 767-783
PMID28341999
show ga
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.
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