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.

Anatomic survey of seeding in Alzheimer's disease brains reveals unexpected patterns.

Tauopathies are heterogeneous neurodegenerative diseases defined by progressive brain accumulation of tau aggregates. The most common tauopathy, sporadic Alzheimer's disease (AD), involves progressive tau deposition that can be divided into specific stages of neurofibrillary tangle pathology. This classification is consistent with experimental data which suggests that network-based propagation is mediated by cell-cell transfer of tau "seeds", or assemblies, that serve as templates for their own replication. Until now, seeding assays of AD brain have largely been limited to areas previously defined by NFT pathology. We now expand this work to additional regions. We selected 20 individuals with AD pathology of NFT stages I, III, and V. We stained and classified 25 brain regions in each using the anti-phospho-tau monoclonal antibody AT8. We measured tau seeding in each of the 500 samples using a cell-based tau "biosensor" assay in which induction of intracellular tau aggregation is mediated by exogenous tau assemblies. We observed a progressive increase in tau seeding according to NFT stage. Seeding frequently preceded NFT pathology, e.g., in the basolateral subnucleus of the amygdala and the substantia nigra, pars compacta. We observed seeding in brain regions not previously known to develop tau pathology, e.g., the globus pallidus and internal capsule, where AT8 staining revealed mainly axonal accumulation of tau. AT8 staining in brain regions identified because of tau seeding also revealed pathology in a previously undescribed cell type: Bergmann glia of the cerebellar cortex. We also detected tau seeding in brain regions not previously examined, e.g., the intermediate reticular zone, dorsal raphe nucleus, amygdala, basal nucleus of Meynert, and olfactory bulb. In conclusion, tau histopathology and seeding are complementary analytical tools. Tau seeding assays reveal pathology in the absence of AT8 signal in some instances, and previously unrecognized sites of tau deposition. The variation in sites of seeding between individuals could underlie differences in the clinical presentation and course of AD.