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Amyloid-β pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo

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Abstract

Neuropathological analysis in Alzheimer’s disease (AD) and experimental evidence in transgenic models overexpressing frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) mutant tau suggest that amyloid-β pathology enhances the development of tau pathology. In this work, we analyzed this interaction independently of the overexpression of an FTDP-17 mutant tau, by analyzing tau pathology in wild-type (WT), 5xFAD, APP−/− and tau−/− mice after stereotaxic injection in the somatosensory cortex of short-length native human AD-PHF. Gallyas and phosphotau-positive tau inclusions developed in WT, 5xFAD, and APP−/− but not in tau−/− mice. Ultrastructural analysis demonstrated their intracellular localization and that they were composed of straight filaments. These seeded tau inclusions were composed only of endogenous murine tau exhibiting a tau antigenic profile similar to tau aggregates in AD. Insoluble tau level was higher and ipsilateral anteroposterior and contralateral cortical spreading of tau inclusions was more important in AD-PHF-injected 5xFAD mice than in WT mice. The formation of large plaque-associated dystrophic neurites positive for oligomeric and phosphotau was observed in 5xFAD mice injected with AD-PHF but never in control-injected or in non-injected 5xFAD mice. An increased level of the p25 activator of CDK5 kinase was found in AD-PHF-injected 5xFAD mice. These data demonstrate in vivo that the presence of Aβ pathology enhances experimentally induced tau seeding of endogenous, wild-type tau expressed at physiological level, and demonstrate the fibrillar nature of heterotopically seeded endogenous tau. These observations further support the hypothesis that Aβ enhances tau pathology development in AD through increased pathological tau spreading.

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Acknowledgements

This study was supported by grants from the Belgian Fonds de la Recherche Scientifique Médicale (T.0023.15, T.0027.19), the Fund Aline (King Baudouin Foundation), the Foundation for Alzheimer Research (FRA/SAO) and the Génicot Fund. 3-D Deep imaging was performed in the Neurophysiology Laboratory and Light Microscopy Facility, Faculty of Medicine, Université Libre de Bruxelles. We thank Dr. Jean-Nöel Octave for the 3H5 antibody, Dr. Peter Davies for PHF1, Alz50 and MC1 antibodies, and Dr. Rakez Kayed for tau T22 antibody.

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  1. Laboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Faculty of Medicine, Université Libre de Bruxelles, 808, route de Lennik, Bldg GE, 1070, Brussels, Belgium

    Cristina Vergara, Sarah Houben, Valérie Suain, Zehra Yilmaz, Robert De Decker, Virginie Vanden Dries, Alain Boom, Salwa Mansour, Karelle Leroy, Kunie Ando & Jean-Pierre Brion

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  1. Cristina Vergara
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Vergara, C., Houben, S., Suain, V. et al. Amyloid-β pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo. Acta Neuropathol 137, 397–412 (2019). https://doi.org/10.1007/s00401-018-1953-5

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