title: The Streptomyces metabolite anhydroexfoliamycin ameliorates hallmarks of Alzheimer's disease in vitro and in vivo.
abstract: Anhydroexfoliamycin (1) and undecylprodigiosin (2) have been previously described as neuroprotective molecules against oxidative stress in neurons. Since oxidative stress is strongly correlated with neurodegenerative diseases, we have evaluated their effects over the principal hallmarks of Alzheimer's disease (AD). Both compounds were tested in vitro in two different neuroblastoma cellular models, one for amyloid precursor protein metabolism studies (BE(2)-M17) and another one specific for taupathology in AD (SH-SY5Y-TMHT441). Amyloid-beta (Aβ) levels, β-secretase (BACE1) activity, tau phosphorylation, extracellular signal-regulated kinase (ERK) and glycogen synthase kinase-3beta (GSK3β) expression were analyzed and while undecylprodigiosin (2) produced poor results, anhydroexfoliamycin (1) strongly inhibited GSK3β, reducing tau phosphorylation in vitro (0.1 μM). A competitive assay of anhydroexfoliamycin (1) and the specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, showed that the reduction of the phosphorylated tau levels is mediated by the JNK pathway in SH-SY5Y-TMHT441 cells. Thus, this compound was tested in vivo by intraperitoneal administration in 3xTg-AD mice, confirming the positive results registered in the in vitro assays. This work presents anhydroexfoliamycin (1) as a promising candidate for further studies in drug development against neurodegenerative diseases.
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Leirós
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Alonso
authors.affiliation: Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, Scotland, UK; Pharmacognosy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 32514, Egypt.
authors.forename: M E
authors.initials: ME
authors.lastname: Rateb
authors.affiliation: Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, Scotland, UK.
authors.forename: R
authors.initials: R
authors.lastname: Ebel
authors.affiliation: Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, Scotland, UK.
authors.forename: M
authors.initials: M
authors.lastname: Jaspars
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Alfonso
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain. Electronic address: Luis.Botana@usc.es.
authors.forename: L M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000873:Anthracenes / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000737:chemistry / Q000627:therapeutic use*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D011353:Prodigiosin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D016875:tau Proteins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000873:Anthracenes; D014150:Antipsychotic Agents; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C432165:pyrazolanthrone; C047347:undecylprodigiosin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D020930:MAP Kinase Kinase Kinases; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D011353:Prodigiosin
keywords: 3xTg-AD; Alzheimer disease; anhydroexfoliamycin; glycogen synthase kinase-3beta; streptomyces; β-secretase