Journal
ACTA NEUROPATHOLOGICA
Volume 127, Issue 5, Pages 667-683Publisher
SPRINGER
DOI: 10.1007/s00401-014-1254-6
Keywords
Tau; Aggregation; Propagation; Prion; Transgenic mouse line; Human P301S tau
Categories
Funding
- Swiss National Foundation [310030_135214]
- VELUX Foundation
- U.K.'s Medical Research Council [U105184291]
- Swiss National Science Foundation (SNF) [310030_135214] Funding Source: Swiss National Science Foundation (SNF)
- Parkinson's UK [K-1012] Funding Source: researchfish
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Intracellular inclusions composed of hyperphosphorylated filamentous tau are a hallmark of Alzheimer's disease, progressive supranuclear palsy, Pick's disease and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates do not only seed further tau aggregation within neurons, but can also spread to neighbouring cells and functionally connected brain regions. This process is referred to as 'tau propagation' and may explain the stereotypic progression of tau pathology in the brains of Alzheimer's disease patients. Here, we describe a novel in vivo model of tau propagation using human P301S tau transgenic mice infused unilaterally with brain extract containing tau aggregates. Infusion-related neurofibrillary tangle pathology was first observed 2 weeks post-infusion and increased in a stereotypic, time-dependent manner. Contralateral and anterior/posterior spread of tau pathology was also evident in nuclei with strong synaptic connections (efferent and afferent) to the site of infusion, indicating that spread was dependent on synaptic connectivity rather than spatial proximity. This notion was further supported by infusion-related tau pathology in white matter tracts that interconnect these regions. The rapid and robust propagation of tau pathology in this model will be valuable for both basic research and the drug discovery process.
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