Tau seeds from Alzheimer's disease brains trigger tau spread in macaques while oligomeric-Aβ mediates pathology maturation.

Autor: Darricau M; Univ. Bordeaux, CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France., Dou C; NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, National Center for Technology and Innovation of Animal Model, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS), Beijing, P.R. China., Kinet R; Univ. Bordeaux, CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France., Zhu T; NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, National Center for Technology and Innovation of Animal Model, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS), Beijing, P.R. China., Zhou L; NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, National Center for Technology and Innovation of Animal Model, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS), Beijing, P.R. China., Li X; NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, National Center for Technology and Innovation of Animal Model, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS), Beijing, P.R. China., Bedel A; CHU de Bordeaux, Service de biochimie, Bordeaux, Univ. Bordeaux, Bordeaux, France., Claverol S; Univ. Bordeaux, Bordeaux Proteome, Bordeaux, France., Tokarski C; Univ. Bordeaux, Bordeaux Proteome, Bordeaux, France., Katsinelos T; UK Dementia Research Institute, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., McEwan WA; UK Dementia Research Institute, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Zhang L; NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, National Center for Technology and Innovation of Animal Model, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS), Beijing, P.R. China., Gao R; NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, National Center for Technology and Innovation of Animal Model, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS), Beijing, P.R. China., Bourdenx M; UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London, UK., Dehay B; Univ. Bordeaux, CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France., Qin C; NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, National Center for Technology and Innovation of Animal Model, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS), Beijing, P.R. China.; Changping National laboratory (CPNL), Beijing, China., Bezard E; Univ. Bordeaux, CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France.; Motac Neuroscience, Floirac, France., Planche V; Univ. Bordeaux, CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France.; CHU de Bordeaux, Pôle de Neurosciences Cliniques, Centre Mémoire de Ressources et de Recherche, Bordeaux, France.
Jazyk: angličtina
Zdroj: Alzheimer's & dementia : the journal of the Alzheimer's Association [Alzheimers Dement] 2024 Mar; Vol. 20 (3), pp. 1894-1912. Date of Electronic Publication: 2023 Dec 26.
DOI: 10.1002/alz.13604
Abstrakt: Introduction: The "prion-like" features of Alzheimer's disease (AD) tauopathy and its relationship with amyloid-β (Aβ) have never been experimentally studied in primates phylogenetically close to humans.
Methods: We injected 17 macaques in the entorhinal cortex with nanograms of seeding-competent tau aggregates purified from AD brains or control extracts from aged-matched healthy brains, with or without intracerebroventricular co-injections of oligomeric-Aβ.
Results: Pathological tau injection increased cerebrospinal fluid (CSF) p-tau181 concentration after 18 months. Tau pathology spreads from the entorhinal cortex to the hippocampal trisynaptic loop and the cingulate cortex, resuming the experimental progression of Braak stage I to IV. Many AD-related molecular networks were impacted by tau seeds injections regardless of Aβ injections in proteomic analyses. However, we found mature neurofibrillary tangles, increased CSF total-tau concentration, and pre- and postsynaptic degeneration only in Aβ co-injected macaques.
Discussion: Oligomeric-Aβ mediates the maturation of tau pathology and its neuronal toxicity in macaques but not its initial spreading.
Highlights: This study supports the "prion-like" properties of misfolded tau extracted from AD brains. This study empirically validates the Braak staging in an anthropomorphic brain. This study highlights the role of oligomeric Aβ in driving the maturation and toxicity of tau pathology. This work establishes a novel animal model of early sporadic AD that is closer to the human pathology.
(© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
Databáze: MEDLINE
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