title: Rifampicin is a candidate preventive medicine against amyloid-β and tau oligomers.
abstract: Amyloid-β, tau, and α-synuclein, or more specifically their soluble oligomers, are the aetiologic molecules in Alzheimer's disease, tauopathies, and α-synucleinopathies, respectively. These proteins have been shown to interact to accelerate each other's pathology. Clinical studies of amyloid-β-targeting therapies in Alzheimer's disease have revealed that the treatments after disease onset have little benefit on patient cognition. These findings prompted us to explore a preventive medicine which is orally available, has few adverse effects, and is effective at reducing neurotoxic oligomers with a broad spectrum. We initially tested five candidate compounds: rifampicin, curcumin, epigallocatechin-3-gallate, myricetin, and scyllo-inositol, in cells expressing amyloid precursor protein (APP) with the Osaka (E693Δ) mutation, which promotes amyloid-β oligomerization. Among these compounds, rifampicin, a well-known antibiotic, showed the strongest activities against the accumulation and toxicity (i.e. cytochrome c release from mitochondria) of intracellular amyloid-β oligomers. Under cell-free conditions, rifampicin inhibited oligomer formation of amyloid-β, tau, and α-synuclein, indicating its broad spectrum. The inhibitory effects of rifampicin against amyloid-β and tau oligomers were evaluated in APPOSK mice (amyloid-β oligomer model), Tg2576 mice (Alzheimer's disease model), and tau609 mice (tauopathy model). When orally administered to 17-month-old APPOSK mice at 0.5 and 1 mg/day for 1 month, rifampicin reduced the accumulation of amyloid-β oligomers as well as tau hyperphosphorylation, synapse loss, and microglial activation in a dose-dependent manner. In the Morris water maze, rifampicin at 1 mg/day improved memory of the mice to a level similar to that in non-transgenic littermates. Rifampicin also inhibited cytochrome c release from the mitochondria and caspase 3 activation in the hippocampus. In 13-month-old Tg2576 mice, oral rifampicin at 0.5 mg/day for 1 month decreased amyloid-β oligomer accumulation, tau hyperphosphorylation, synapse loss, and microglial activation, but not amyloid deposition. Rifampicin treatment to 14-15-month-old tau609 mice at 0.5 and 1 mg/day for 1 month also reduced tau oligomer accumulation, tau hyperphosphorylation, synapse loss, and microglial activation in a dose-dependent fashion, and improved the memory almost completely at 1 mg/day. In addition, rifampicin decreased the level of p62/sequestosome-1 in the brain without affecting the increased levels of LC3 (microtubule-associated protein light chain 3) conversion, suggesting the restoration of autophagy-lysosomal function. Considering its prescribed dose and safety in humans, these results indicate that rifampicin could be a promising, ready-to-use medicine for the prevention of Alzheimer's disease and other neurodegenerative diseases.
authors.affiliation: Department of Neuroscience, Osaka City University Graduate School of Medicine, Osaka, Japan Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Umeda
authors.affiliation: Department of Neurology and Neurobiology and Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Ono
authors.affiliation: Department of Neuroscience, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Sakai
authors.affiliation: Department of Neuroscience, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Minato
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Laboratory of Structual Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Mineyuki
authors.initials: M
authors.lastname: Mizuguchi
authors.affiliation: Department of Neurobiology, Weinberg College of Arts and Science, Northwestern University, Evanston, IL, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Klein
authors.affiliation: Department of Neurology and Neurobiology and Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan Department of Clinical Neuroscience, Osaka City University Medical School, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Neuroscience, Osaka City University Graduate School of Medicine, Osaka, Japan Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan tomi@med.osaka-cu.ac.jp.
authors.forename: Takami
authors.initials: T
authors.lastname: Tomiyama
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000150:complications / Q000188:drug therapy; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D012293:Rifampin / Q000494:pharmacology* / Q000627:therapeutic use*; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D013569:Synapses / Q000187:drug effects; D051843:Synucleins / Q000187:drug effects / Q000378:metabolism; D024801:Tauopathies / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D016875:tau Proteins / Q000187:drug effects* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D000071456:Sequestosome-1 Protein; D051843:Synucleins; D016875:tau Proteins; D045304:Cytochromes c; D053148:Caspase 3; D012293:Rifampin
keywords: autophagy; mitochondria; neurodegenerative disease; oligomer; prevention