Tau seeding without tauopathy.

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 can efficiently propagate unique, transmissible tau pathologies. This suggests a dedicated cellular replication machinery, potentially reflecting a normal physiologic function for tau seeds. Consequently, we hypothesized that healthy control brains would contain 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 to 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 wildtype 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, real-time quaking-induced conversion, 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 nonpathogenic conditions may reflect a normal function that goes awry in disease states.

Tau seeding in cases of multiple sclerosis.

Relapsing remitting multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system that in many cases leads to progressive MS, a neurodegenerative disease. Progressive MS is untreatable and relentless, and its cause is unknown. Prior studies of MS have documented neuronal accumulation of phosphorylated tau protein, which characterizes another heterogeneous group of neurogenerative disorders, the tauopathies. Known causes of tauopathy are myriad, and include point mutations within the tau gene, amyloid beta accumulation, repeated head trauma, and viral infection. We and others have proposed that tau has essential features of a prion. It forms intracellular assemblies that can exit a cell, enter a secondary cell, and serve as templates for their own replication in a process termed "seeding." We have previously developed specialized "biosensor" cell systems to detect and quantify tau seeds in brain tissues. We hypothesized that progressive MS is a tauopathy, potentially triggered by inflammation. We tested for and detected tau seeding in frozen brain tissue of 6/8 subjects with multiple sclerosis. We then evaluated multiple brain regions from a single subject for whom we had detailed clinical history. We observed seeding outside of MS plaques that was enriched by immunopurification with two anti-tau antibodies (HJ8.5 and MD3.1). Immunohistochemistry with AT8 and MD3.1 confirmed prior reports of tau accumulation in MS. Although larger studies are required, our data suggest that progressive MS may be considered a secondary tauopathy.