Immunological memory to hyperphosphorylated tau in asymptomatic individuals

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 materialThe online version of this article (doi:10.1007/s00401-017-1705-y) contains supplementary material, which is available to authorized users.

Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration

“…Tau mutations result in tauopathies, such as corticobasal degeneration and frontotemporal dementia (FTD), but not AD (Morris, Lee, & Wood, ). However, hyperphosphorylated tau protein is considered an important target for the treatment of AD as it correlates with symptomatology (Panza et al, ; Pascual et al, ; Sigurdsson, ).…”

Autoantibodies against the prion protein in individuals with PRNP mutations

“…Naturally occurring autoantibodies against hyperphosphorylated tau protein have been isolated from several asymptomatic blood donors. 40 Researchers from Neurimmune (Schlieren, Switzerland) recently reported the development of a fully human antibody against amyotrophic lateral sclerosis targeting pathologically misfolded SOD1, α-miSOD1, from a memory B-cell library from healthy elderly individuals. 41 Phase III trials involving aducanumab, a bona fide human antibody with potent β-amyloid clearing capabilities, were stopped prematurely.…”

Single-cell Screening Method for the Selection and Recovery of Antibodies with Desired Specificities from Enriched Human Memory B Cell Populations

“…The use of linear peptides is likely not optimal, since it may limit the identification of antibodies against non-linear or structural epitopes. However, we were able to identify several unique antibodies against tau and these are currently undergoing further evaluation 8,9 . Another limitation is the low throughput of the molecular biology recovery and cloning of IgGs.…”

“…Currently, there are methods being developed to connect the enormous amount of data collected from next generation sequencing with functional analysis of antigen specificity, but these methods are still being refined. Despite its limitations, the method described here has been used to identify antibodies with potential therapeutic value for both infectious and non-infectious diseases 8,14,15 , and represents a reliable approach to recover relevant antigen-specific IgGs from humans, without extensive manipulation of B cells or extensive cell culture.…”