Tau seeding without tauopathy

Neurodegenerative tauopathies such as Alzheimers disease (AD) are caused by brain accumulation of tau assemblies. Evidence suggests tau functions as a prion, and cells and animals efficiently propagate unique tau assemblies. This suggests a dedicated cellular replication machinery, with normal physiologic function for tau seeds. Consequently, we hypothesized that healthy control brains would have seeding activity. We 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 ranging 19-65 years. We detected seeding in the parietal cortex, but not in the cerebellum, or in 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. 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. Taus ability to adopt self-replicating conformations under non-pathogenic conditions may reflect normal function that goes awry in disease states.