title: Chronic consumption of Annona muricata juice triggers and aggravates cerebral tau phosphorylation in wild-type and MAPT transgenic mice.
abstract: In the pathogenesis of tauopathies, genetic and environmental factors have been identified. While familial clustering led to the identification of mutations in MAPT encoding the microtubule-associated protein tau, the high incidence of a sporadic tauopathy endemic in Guadeloupe was linked to the plant-derived mitochondrial complex I inhibitor annonacin. The interaction of both factors was studied in the present work in a realistic paradigm over a period of 12 months. Mice over-expressing either human wild-type tau or R406W mutant tau as well as non-transgenic mice received either regular drinking water or commercially available tropical fruit juice made of soursop (Annona muricata L.) as dietary source of neurotoxins. HPLC-MS analysis of this juice identified several Annonaceous acetogenins, mainly annonacin (16.2 mg/L), and 41 isoquinoline alkaloids (18.0 mg/L, mainly asimilobine and reticuline). After 12 month of juice consumption, several brain regions showed an increased number of neurons with phosphorylated tau in the somatodendritic compartment of R406W mice and, to a much lesser extent, of non-transgenic mice and mice over-expressing human wild-type tau. Moreover, juice drinking was associated with a reduction in synaptophysin immunoreactivity, as well as an increase in 3-nitrotyrosine (3NT) reactivity in all three genotypes. The increase in 3NT suggests that Annona muricata juice promotes the generation of reactive nitrogen species. This study provides first experimental evidence that long-lasting oral ingestion of a widely consumed environmental factor can induce somatodendritic accumulation of hyperphosphorylated tau in mice expressing rodent or human wild-type tau, and can accelerate tau pathology in R406W-MAPT transgenic mice.
authors: Experimental Neurology, University of Marburg, Marburg, Germany.
authors: Robert
authors: R
authors: Rottscholl
authors: Experimental Neurology, University of Marburg, Marburg, Germany.
authors: Marlen
authors: M
authors: Haegele
authors: Experimental Neurology, University of Marburg, Marburg, Germany.
authors: Britta
authors: B
authors: Jainsch
authors: Experimental Neurology, University of Marburg, Marburg, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors: Hong
authors: H
authors: Xu
authors: Experimental Neurology, University of Marburg, Marburg, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Department of Neurology, Technical University Munich, Munich, Germany.
authors: Gesine
authors: G
authors: Respondek
authors: Experimental Neurology, University of Marburg, Marburg, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Department of Neurology, Technical University Munich, Munich, Germany.
authors: Matthias
authors: M
authors: Höllerhage
authors: Experimental Neurology, University of Marburg, Marburg, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors: Thomas W
authors: TW
authors: Rösler
authors: Laboratoire de Pharmacognosie, BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, UFR Pharmacie, Châtenay-Malabry, France.
authors: Emilie
authors: E
authors: Bony
authors: Laboratoire de Pharmacognosie, BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, UFR Pharmacie, Châtenay-Malabry, France.
authors: Jessica
authors: J
authors: Le Ven
authors: Centre de recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette, France.
authors: Vincent
authors: V
authors: Guérineau
authors: Centre de recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette, France.|Normandie Université, COBRA, UMR 6014 et FR3038, Université de Rouen; INSA de Rouen; CNRS, IRCOF, Mont-Saint-Aignan Cedex, France.
authors: Isabelle
authors: I
authors: Schmitz-Afonso
authors: Laboratoire de Pharmacognosie, BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, UFR Pharmacie, Châtenay-Malabry, France.
authors: Pierre
authors: P
authors: Champy
authors: Experimental Neurology, University of Marburg, Marburg, Germany.
authors: Wolfgang H
authors: WH
authors: Oertel
authors: Experimental Neurology, University of Marburg, Marburg, Germany.|Laboratory of Experimental Neuropathology-ICB, João de Barros Barreto University Hospital, Federal University of Pará, Belém, Brazil.
authors: Elizabeth S
authors: ES
authors: Yamada
authors: Experimental Neurology, University of Marburg, Marburg, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Department of Neurology, Technical University Munich, Munich, Germany.
authors: Günter U
authors: GU
authors: Höglinger
mesh_terms: D000818:Animals; D031041:Annona / Q000009:adverse effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D000067030:Fruit and Vegetable Juices / Q000009:adverse effects; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D010936:Plant Extracts / Q000008:administration & dosage* / Q000009:adverse effects; D011897:Random Allocation; D016875:tau Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C558298:Mapt protein, mouse; D010936:Plant Extracts; D016875:tau Proteins
keywords: R406W; annonacin; environmental neurotoxin; microtubule-associated protein tau; neurodegeneration; tauopathy