Tau seeding without tauopathy

Abstract

Neurodegenerative tauopathies such as Alzheimer’s disease (AD) are caused by brain accumulation of tau assemblies. Evidence suggests tau functions as a prion, and cells and animals efficiently propagate unique, transmissible tau pathology. This suggests a dedicated cellular replication machinery, potentially with a normal physiologic function for tau seeds. Consequently, we hypothesized that healthy control brains would have seeding activity. We have recently developed a novel monoclonal antibody (MD3.1) specific for tau seeds. We used this antibody to immunopurify tau from the parietal and cerebellar cortices of 19 healthy subjects without any neuropathology, ranging 19-65 years. We detected seeding in lysates from the parietal cortex, but not in the cerebellum. We also detected no seeding in brain homogenates from wild-type or human tau knockin mice, suggesting that cellular/genetic context dictates development of seed-competent tau. Seeding did not correlate with subject age or brain tau levels. We confirmed our essential findings using an orthogonal assay, RTQuIC, which amplifies tau seeds in vitro. Dot blot analyses revealed no AT8 immunoreactivity above background levels in parietal and cerebellar extracts and ∼1/100 of that present in AD. Based on binding to a panel of antibodies, the conformational characteristics of control seeds differed from AD, suggesting a unique underlying assembly, or structural ensemble. Tau’s ability to adopt self-replicating conformations under non-pathogenic conditions may reflect a normal function that goes awry in disease states.