Rifampicin is a candidate preventive medicine against amyloid-β and tau oligomers

• Published in: Brain (London, England : 1878) England : 1878), 2016-05, Vol.139 (Pt 5), p.1568-1586
• Main Authors: Umeda, Tomohiro, Ono, Kenjiro, Sakai, Ayumi, Yamashita, Minato, Mizuguchi, Mineyuki, Klein, William L, Yamada, Masahito, Mori, Hiroshi, Tomiyama, Takami
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - complications; Alzheimer Disease - metabolism; Alzheimer Disease - prevention & control; Amyloid beta-Peptides - drug effects; Amyloid beta-Peptides - metabolism; Animals; Caspase 3 - metabolism; Cells, Cultured; Cytochromes c - metabolism; Dose-Response Relationship, Drug; Female; Hippocampus - metabolism; Maze Learning - drug effects; Memory Disorders - complications; Memory Disorders - drug therapy; Mice; Mice, Transgenic; Microglia - drug effects; Microtubule-Associated Proteins - metabolism; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Phosphorylation - drug effects; Rifampin - pharmacology; Rifampin - therapeutic use; Sequestosome-1 Protein - metabolism; Synapses - drug effects; Synucleins - drug effects; Synucleins - metabolism; tau Proteins - drug effects; tau Proteins - metabolism; Tauopathies - complications; Tauopathies - metabolism; Tauopathies - prevention & control
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/aww042

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 a