What is it about?

The presence of hyperphosphorylated tau and the spreading of tau aggregates within the CNS is widely believe to be responsible for driving the progression of pathology in Alzheimer's disease and in a group of neurodegenerative diseases termed tauopathies. The current study describes the ability of a clinical phospho-S396 specific anti-tau antibody, and 6 other tau antibodies binding to epitopes spanning major regions of tau, to interact with pathological tau aggregate species purified from human diseased brain tissue. Brain tissue was obtained from mid-to-late stage Alzheimer's disease (50 samples), as well as from different tauopathies (e.g., CBD, PSP and Pick's disease, 30+ samples) and the purpose was to identify if the human material displayed heterogenous epitope display and if the pS396 antibody was able to consistently interact with and remove pathological tau by immuno-depletion. The conclusion was that different antibodies showed different abilities to interact with pathological tau aggregates. For instance antibodies binding to the repeat domains of tau (the part that forms the core of the aggregates), showed poor ability to interact with aggregated form, whereas the pS396 antibody bound more selectively to aggregated forms of tau and less to monomeric forms, and yet other antibodies (e.g., binding to the N-terminus of tau), bound both aggregated and monomeric forms of tau. The data highlighted that the pS396 antibody consistently was able to efficiently bind to aggregated forms of tau across all disease and across all samples, showing that the individual samples did not show heterogeneity in phosphorylation for this particular tau epitope.

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Why is it important?

Published literature describe that phosphorylation of many different tau epitopes are detectable to different extend at different stages of Alzheimer's disease or across different patient samples, and overall the literature on which tau phospho-epitopes are linked to pathology and at which stage of disease is not very consistent. The original intent of this study was to explore if the phosphorylation of S396 of tau was observed consistently across all patient samples derived from different tauopathies. The result was clear, in the sense that if tau aggregates were present in a given brain sample from a tauopathy, phosphorylation of S396 was proportionally present and the clinical pS396 antibody (hC10.2) was able to efficiently immunodeplete aggregated tau and also deplete seeding activity from all samples. This strengthened the belief that this particular antibody (hC10.2) is well suited as a therapeutic antibody, as the epitope it is targeting is always a feature of pathological tau species and is available for antibody binding.


The data shows that not all tau epitopes in a tau aggregate is available for antibody binding and that some antibodies have a better ability to bind tau aggregates than others. In this study only depletion of aggregates were shown and both N-terminal and C-terminal antibodies were efficient in depletion tau aggregates. But it has previously been shown that if antibodies instead are tested in a direct seeding paradigm, where seeds+antibodies are applied directly to cells , C-terminal antibodies (hC10.2) and other antibodies binding closer to the repeat domains of tau efficiently prevent seeding, whereas N-terminal antibodies do not prevent seeding. This is important, as all the antibodies that have failed in clinical trials so far has been N-terminal tau antibodies. Whether antibodies that do prevent experimental seeding will work in the clinic will still have to be explored, but the therapeutic potential is still there.

Jeppe Falsig
H Lundbeck A/S

Read the Original

This page is a summary of: Highly Specific and Sensitive Target Binding by the Humanized pS396-Tau Antibody hC10.2 Across a Wide Spectrum of Alzheimer’s Disease and Primary Tauopathy Postmortem Brains, Journal of Alzheimer s Disease, June 2022, IOS Press,
DOI: 10.3233/jad-220125.
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