title: Efficient four-drug cocktail therapy targeting amyloid-β peptide for Alzheimer's disease.
abstract: Cocktail treatment is an effective multidrug medication therapy for some diseases, such as cancer and AIDS, because of the additive or synergistic effect of each medicine and relief from adverse effects. Amyloid-β peptide (Aβ), which is now recognized as central to the development of Alzheimer's disease (AD), is derived from the sequential proteolysis of amyloid precursor protein (APP) by β- and γ-secretases. Secretase inhibitors are one of most attractive targets for therapeutic intervention in AD. However, because β- and γ-secretases cleave not only APP but also other substrate proteins, strong inhibition of these secretases leads to severe adverse effects. Some nonsteroidal antiinflammatory drugs (NSAIDs) and cholesterol-lowering drugs (statins) can modify the production of Aβ. Here, we report that a cocktail treatment with four drugs (NSAID, statin, and β- and γ-secretase inhibitors) had additive effects on the reduction of Aβ levels in cultured cells without competing with each other. Moreover, the four-drug cocktail treatment caused no changes in processing of the γ-secretase substrate Notch. This is suggests that this cocktail treatment could be a new therapeutic approach for AD.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Saitama, Japan. asai@saitama-med.ac.jp
authors.forename: Masashi
authors.initials: M
authors.lastname: Asai
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Kei
authors.initials: K
authors.lastname: Maruyama
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051880:Receptors, Notch / Q000187:drug effects; D019821:Simvastatin / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D051880:Receptors, Notch; D019821:Simvastatin; D053829:Amyloid Precursor Protein Secretases