title: Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease.
abstract: Aβ accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that the process of Aβ nucleated polymerization is essential for Aβ fibril formation, pathology spreading and toxicity. Therefore, targeting this process represents an effective therapeutic strategy to slow or block disease progression. To discover compounds that might interfere with the Aβ seeding capacity, toxicity and pathology spreading, we screened a focused library of FDA-approved drugs in vitro using a seeding polymerization assay and identified small molecule inhibitors that specifically interfered with Aβ seeding-mediated fibril growth and toxicity. Mitoxantrone, bithionol and hexachlorophene were found to be the strongest inhibitors of fibril growth and protected primary cortical neuronal cultures against Aβ-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThy1-APPtg mouse model of AD (8-month-old mice). We found that mitoxantrone and bithionol, but not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of Aβ42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and Aβ seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD.
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL) CH-1015 Lausanne, Switzerland; Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Eleuteri
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL) CH-1015 Lausanne, Switzerland.
authors.forename: Saviana
authors.initials: S
authors.lastname: Di Giovanni
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Mante
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Antony
authors.initials: A
authors.lastname: Adame
authors.affiliation: Department of Pathology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Margarita
authors.initials: M
authors.lastname: Trejo
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Wolf
authors.initials: W
authors.lastname: Wrasidlo
authors.affiliation: Laboratory of Molecular and Cellular Biology of Alzheimer's Disease, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.affiliation: Laboratory of Molecular and Cellular Biology of Alzheimer's Disease, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Fraering
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA; Laboratory of Molecular and Cellular Biology of Alzheimer's Disease, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address: emasliah@ucsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL) CH-1015 Lausanne, Switzerland. Electronic address: hilal.lashuel@epfl.ch.
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001735:Bithionol / Q000493:pharmacokinetics / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006582:Hexachlorophene / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008942:Mitoxantrone / Q000493:pharmacokinetics / Q000494:pharmacology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D010446:Peptide Fragments / Q000187:drug effects* / Q000633:toxicity; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D051381:Rats
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D001735:Bithionol; D008942:Mitoxantrone; D006582:Hexachlorophene
keywords: Alzheimer's disease; Amyloid protein; Aβ seeding-mediated aggregation; Aβ-propagation; Drug discovery; Inhibitors