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Stereotaxic injection of fibrillar PHF from Alzheimer brain induces propagation of argyrophilic grains constituted of murine tau in mouse brains

Sarah Houben1, Emilie Audouard1, Caterina Masaracchia1, Zehra Yilmaz1, Valérie Suain1, Michèle Authelet1, Robert De Decker1, Luc Buée2, Alain Boom1, Karelle Leroy1, Kunie Ando1 and Jean-Pierre Brion1*
  • 1 Université Libre de Bruxelles, Faculty of Medicine, ULB Neuroscience Insitute (UNI), Belgium
  • 2 Université de Lille 2, INSERM UMR-S 1172, France

Alzheimer’s disease (AD) is neuropathologically characterized by two hallmarks: extracellular amyloid deposits and intracellular neurofibrillary tangles (NFTs) [7]. The level of NFTs better correlates with cognitive dysfunction than amyloid load. NFTs are composed of hyperphorylated tau proteins that forms paired helical filaments (PHF) [2]. Increasing evidences support the idea that misfolded pathological forms of tau proteins propagate in Prion-like manner [4-6,10]. Indeed in AD brains, tau pathology progression follows neuroanatomically connected pathways, implying cell to cell transmission of pathological tau species to seed endogenous “healthy” tau into pathological tau. But native PHF extracted from human AD brains had never been fully studied for its seeding effects and propagative propensity in vivo. In this study, we aimed to understand the transmission of human AD PHF in the mouse brains of wild-type and THY-Tau22 overexpressing double mutant human tau G272V/P301S [12]. PHF was extracted by sarkosyl fractionation method from an AD case [3,9]. 1 µg of AD PHF was stereotaxically injected into hilus of 3 month-old mice [1]. After 3 months of incubation, wild-type and THY-Tau22 mice developed an atrophy of the dentate gyrus accompanied with argyrophilic grain-like tau pathology characterized by Gallyas silver staining method [11]. Gallyas positive neuropil threads and oligodendroglial coiled bodies were also observed. These grains were mainly constituted of hyperphosphorylated murine tau proteins devoid of human tau. These grains are reminiscent of human argyrophilic grain disease (AgD): these grains were immunoreactive to 4R tau, ubiquitin and p62 [8,13]. These grains were observed in granule cells that extended in the hippocampal hilus and eventually away into the alveus, and the fimbria in injected wild-type and THY-Tau22 mice. Although local hyperphosphorylation of tau was increased in the dentate gyrus of PHF-injected THY-Tau22 mice, the development of NFTs made of mutant human tau was not accelerated in the CA region of hippocampus, indicating that wild-type human PHF were not efficient in seeding tau aggregates made of G272V/P301S mutant human tau. Taken together, stereotaxic injection of human AD PHF into mouse brains caused pathological transmission via conferring wild-type murine tau into an argyrophilic 4R tau pathology [1]. Our data provide an interesting murine model independent of expression of a mutant tau protein. Résumé en Français: Selon une hypothèse, les dégénérescences neurofibrillaires (une des deux lésions caractéristiques de la maladie d’Alzheimer) composées de protéines tau anormalement phosphorylées et agrégées se propageraient de cellule à cellule. Notre étude a eu pour objectif d’étudier le développement et la propagation de ces lésions neurofibrillaires après injection de protéines tau insolubles provenant de patients Alzheimer dans le cerveau de souris sauvages et transgéniques. Nous avons pu observer, 3 mois après injection, une atrophie d’une partie de l’hippocampe, ainsi que des agrégats intracellulaires composés majoritairement par des protéines tau hyperphosphorylées et agrégées. Samenvatting in het Nederlands: De hypothese bestaat dat de neurofibrillaire degeneraties (één van de twee letsels die typisch voorkomen bij de ziekte van Alzheimer) die uit abnormaal gefosforyleerde en geaggregeerde tau proteïne samengesteld zijn zich van de ene naar de andere cel verspreiden. Onze studie had tot doel de ontwikkeling en de verspreiding van deze neurofibrillaire letsels te bestuderen nadat onoplosbare tau proteïnes afkomstig van Alzheimer patiënten in de hersenen van wilde en transgenetische muizen geïnjecteerd waren. Drie maanden na de injectie hebben we een atrofie van een deel van de hippocampus vastgesteld alsook intracellulaire aggregaten aangetroffen die voornamelijk uit hypergefosforyleerde en geaggregeerde tau proteïnes samengesteld waren.

References

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Keywords: nFTS, PHF, Alzheimer’s disease, Argyrophilic grains, tau propagation

Conference: 6th Belgian Brain Congress, MONS, Belgium, 8 Oct - 8 Oct, 2016.

Presentation Type: Poster Presentation

Topic: Brain and brain diseases: between heredity and environment

Citation: Houben S, Audouard E, Masaracchia C, Yilmaz Z, Suain V, Authelet M, De Decker R, Buée L, Boom A, Leroy K, Ando K and Brion J (2016). Stereotaxic injection of fibrillar PHF from Alzheimer brain induces propagation of argyrophilic grains constituted of murine tau in mouse brains. Conference Abstract: 6th Belgian Brain Congress. doi: 10.3389/conf.fnagi.2016.03.00040

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Received: 30 Jun 2016; Published Online: 05 Jul 2016.

* Correspondence: MD, PhD. Jean-Pierre Brion, Université Libre de Bruxelles, Faculty of Medicine, ULB Neuroscience Insitute (UNI), Brussels, 1070, Belgium, jpbrion@ulb.ac.be