title: A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity.
abstract: 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.
authors: Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK, ahmedze@lilly.com.
authors: Zeshan
authors: Z
authors: Ahmed
authors: Jane
authors: J
authors: Cooper
authors: Tracey K
authors: TK
authors: Murray
authors: Katya
authors: K
authors: Garn
authors: Emily
authors: E
authors: McNaughton
authors: Hannah
authors: H
authors: Clarke
authors: Samira
authors: S
authors: Parhizkar
authors: Mark A
authors: MA
authors: Ward
authors: Annalisa
authors: A
authors: Cavallini
authors: Samuel
authors: S
authors: Jackson
authors: Suchira
authors: S
authors: Bose
authors: Florence
authors: F
authors: Clavaguera
authors: Markus
authors: M
authors: Tolnay
authors: Isabelle
authors: I
authors: Lavenir
authors: Michel
authors: M
authors: Goedert
authors: Michael L
authors: ML
authors: Hutton
authors: Michael J
authors: MJ
authors: O'Neill
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D011897:Random Allocation; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D066127:White Matter / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins