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

Zeshan Ahmed,Isabelle Lavenir,Annalisa Cavallini,Mark A Ward,Hannah Clarke,Samuel Jackson,Tracey K Murray,Jane Cooper,Samira Parhizkar,Suchira Bose,Markus Tolnay,Emily Mcnaughton,Katya Garn,Michel Goedert,Florence Clavaguera,Michael L Hutton,Michael J O’Neill

doi:10.1007/s00401-014-1254-6

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1254-6) contains supplementary material, which is available to authorized users.

Highlights

Keywords Tau · Aggregation · Propagation · Prion · Transgenic mouse line · Human P301S tau Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterised by extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) [20], with the latter being composed of microtubule-associated protein tau [6]
Examination at the infusion coordinates 2.5 months postinfusion revealed striking PG-5-positive tau pathology in the hippocampus of P301SBE mice, whereas such pathology was only sparse in age-matched controls (Fig. 1a)
In mice infused with P301SBE, the infused hippocampus had significantly more inclusions than the contralateral hippocampus, whereas no such differences were detected in the wild-type brain extract (WTBE) or phosphate-buffered saline (PBS) groups

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterised by extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) [20], with the latter being composed of microtubule-associated protein tau [6]. Abnormal tau accumulation is characteristic of other neurodegenerative diseases, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick’s disease (PiD), which are collectively termed tauopathies [31]. In AD the severity of NFT pathology correlates with cognitive decline, further supporting the link between tau pathology, functional impairment and neurodegeneration [47]. These studies highlight abnormal tau as a potential therapeutic target and emphasise the need for understanding the molecular

Methods

Results

Discussion

Conclusion