Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life.

Autor: Uhlmann RE; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany.; Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany., Rother C; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany.; Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany., Rasmussen J; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany.; Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany., Schelle J; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany., Bergmann C; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Ullrich Gavilanes EM; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany., Fritschi SK; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany., Buehler A; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany., Baumann F; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany., Skodras A; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany., Al-Shaana R; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany., Beschorner N; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany., Ye L; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany., Kaeser SA; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany., Obermüller U; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany., Christensen S; Department of Biotherapeutic Discovery, H. Lundbeck A/S, Copenhagen, Denmark., Kartberg F; Department of Biotherapeutic Discovery, H. Lundbeck A/S, Copenhagen, Denmark., Stavenhagen JB; Department of Biotherapeutic Discovery, H. Lundbeck A/S, Copenhagen, Denmark., Rahfeld JU; Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Halle, Germany., Cynis H; Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Halle, Germany., Qian F; Biogen Inc., Cambridge, MA, USA., Weinreb PH; Biogen Inc., Cambridge, MA, USA., Bussiere T; Biogen Inc., Cambridge, MA, USA., Walker LC; Department of Neurology and Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA., Staufenbiel M; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Jucker M; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. mathias.jucker@uni-tuebingen.de.; German Center for Neurodegenerative Diseases, Tübingen, Tübingen, Germany. mathias.jucker@uni-tuebingen.de.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2020 Dec; Vol. 23 (12), pp. 1580-1588. Date of Electronic Publication: 2020 Nov 16.
DOI: 10.1038/s41593-020-00737-w
Abstrakt: Amyloid-β (Aβ) deposits are a relatively late consequence of Aβ aggregation in Alzheimer's disease. When pathogenic Aβ seeds begin to form, propagate and spread is not known, nor are they biochemically defined. We tested various antibodies for their ability to neutralize Aβ seeds before Aβ deposition becomes detectable in Aβ precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived Aβ assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of Aβ deposition and downstream pathologies 6 months later. This demonstrates that therapeutically targetable pathogenic Aβ seeds already exist during the lag phase of protein aggregation in the brain. Thus, the preclinical phase of Alzheimer's disease-currently defined as Aβ deposition without clinical symptoms-may be a relatively late manifestation of a much earlier pathogenic seed formation and propagation that currently escapes detection in vivo.
Databáze: MEDLINE
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