Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy

Abstract

Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes. Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain.

Sleep Deprivation Affects Tau Phosphorylation in Human Cerebrospinal Fluid

“…The half‐life of Aβ is ~9 hours in the human central nervous system (CNS) as measured in CSF, and we have recently shown that CSF Aβ increases during sleep deprivation from increased production . Tau in the CNS of humans has a half‐life of ~23 days from the time of translation; however, once tau is released into the brain interstitial fluid or CSF, its half‐life is on the order of hours . Therefore, we hypothesize that increased release rather than increased production accounts for the rise in tau concentration during sleep deprivation.…”

Plasma NT1 Tau is a Specific and Early Marker of Alzheimer's Disease

“…14 Initial efforts focused on assays that did not differentiate between phosphorylated and unphosphorylated tau. [15][16][17][18][19][20][21] Some studies found that tau in plasma was increased in AD, 16,19,22,23 whereas others found no significant change. 19,24 The Quanterix Human Tau kit (erroneously referred to as "total tau") has been the most widely applied assay used to measure tau in plasma.…”

Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

“…Targeting numerous other epitopes has been shown to be effective in several studies. These include non-phosphorylated- [27,30,32,41,42,46–48,69,70], phosphorylated- [20,24,25,27,29,35,39,43,49], conformational-/oligomeric [20,31,33,34,40,44,45], and a truncated epitope [66,71]. Since these studies have various designs, they cannot be easily compared to identify the best epitopes to target.…”