title: Highly potent soluble amyloid-β seeds in human Alzheimer brain but not cerebrospinal fluid.
abstract: The soluble fraction of brain samples from patients with Alzheimer's disease contains highly biologically active amyloid-β seeds. In this study, we sought to assess the potency of soluble amyloid-β seeds derived from the brain and cerebrospinal fluid. Soluble Alzheimer's disease brain extracts were serially diluted and then injected into the hippocampus of young, APP transgenic mice. Eight months later, seeded amyloid-β deposition was evident even when the hippocampus received subattomole amounts of brain-derived amyloid-β. In contrast, cerebrospinal fluid from patients with Alzheimer's disease, which contained more than 10-fold higher levels of amyloid-β peptide than the most concentrated soluble brain extracts, did not induce detectable seeding activity in vivo. Similarly, cerebrospinal fluid from aged APP-transgenic donor mice failed to induce cerebral amyloid-β deposition. In comparison to the soluble brain fraction, cerebrospinal fluid largely lacked N-terminally truncated amyloid-β species and exhibited smaller amyloid-β-positive particles, features that may contribute to the lack of in vivo seeding by cerebrospinal fluid. Interestingly, the same cerebrospinal fluid showed at least some seeding activity in an in vitro assay. The present results indicate that the biological seeding activity of soluble amyloid-β species is orders of magnitude greater in brain extracts than in the cerebrospinal fluid.
authors.affiliation: German Centre for Neurodegenerative Diseases (DZNE), Tübingen, D-72076 Tübingen, Germany.|Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany.|Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, D-72074 Tübingen, Germany.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Fritschi
authors.affiliation: German Centre for Neurodegenerative Diseases (DZNE), Tübingen, D-72076 Tübingen, Germany.|Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Langer
authors.affiliation: German Centre for Neurodegenerative Diseases (DZNE), Tübingen, D-72076 Tübingen, Germany.|Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Kaeser
authors.affiliation: German Centre for Neurodegenerative Diseases (DZNE), Tübingen, D-72076 Tübingen, Germany.|Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Maia
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, S-43180 Mölndal, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Pinotsi
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Clemens F
authors.initials: CF
authors.lastname: Kaminski
authors.affiliation: Department of Neurology and Institute of Pathology, University Hospital Basel, CH-4003 Basel, Switzerland.
authors.forename: David T
authors.initials: DT
authors.lastname: Winkler
authors.affiliation: German Centre for Neurodegenerative Diseases (DZNE), Tübingen, D-72076 Tübingen, Germany.|Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany.|Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Maetzler
authors.affiliation: Institute of Neuropathology, Faculty of Medicine, University of Duisburg-Essen, D-45147 Essen, Germany.
authors.forename: Kathy
authors.initials: K
authors.lastname: Keyvani
authors.affiliation: Department of Psychiatry and Psychotherapy, Faculty of Medicine, University of Duisburg-Essen, D-45147 Essen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Spitzer
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Centre, D-37075 Göttingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Wiltfang
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Gabriele S
authors.initials: GS
authors.lastname: Kaminski Schierle
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, S-43180 Mölndal, Sweden.|UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: German Centre for Neurodegenerative Diseases (DZNE), Tübingen, D-72076 Tübingen, Germany.|Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.affiliation: German Centre for Neurodegenerative Diseases (DZNE), Tübingen, D-72076 Tübingen, Germany.|Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid / Q000737:chemistry; D011897:Random Allocation; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments
keywords: amyloid; biomarker; dementia; seeding