title: Testing the therapeutic potential of doxycycline in a Drosophila melanogaster model of Alzheimer disease.
abstract: Therapies for Alzheimer disease that reduce the production of pathogenic amyloid β (Aβ) peptides have been associated with a range of unwanted effects. For this reason, alternative strategies that promote the clearance of the peptide by preventing its aggregation and deposition in the brain have been favored. In this context we have studied doxycycline, a member of the tetracycline family of antibiotics that has shown neuroprotective effects in a number of models of neurodegenerative disease. We investigated the neuroprotective potential of doxycycline in a Drosophila model of Aβ toxicity and sought to correlate any effects with the aggregation state of the peptide. We found that administration of doxycycline to Aβ42-expressing flies did not improve their lifespan but was able to slow the progression of their locomotor deficits. We also measured the rough eye phenotype of transgenic flies expressing the E22G variant of Aβ42 and showed that doxycycline administration partially rescued the toxicity of Aβ in the developing eye. We correlated these in vivo effects with in vitro observations using transmission electron microscopy, dynamic light scattering, and thioflavin T binding. We found that doxycycline prevents Aβ fibrillization and favors the generation of smaller, non-amyloid structures that were non-toxic as determined by the lack of caspase 3 activation in a neuroblastoma cell line. Our confirmation that doxycycline can prevent amyloid β toxicity both in vitro and in vivo supports its therapeutic potential in AD.
authors: Molecular Neurobiology Unit, Instituto de Biologia Molecular e Celular (IBMC), Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
authors: Rita
authors: R
authors: Costa
authors: University of Cambridge, Department of Genetics, Downing Street, CB2 3EH, United Kingdom, and the Cambridge Institute for Medical Research, Hills Road, CB2 0XY, United Kingdom.
authors: Elena
authors: E
authors: Speretta
authors: University of Cambridge, Department of Genetics, Downing Street, CB2 3EH, United Kingdom, and the Cambridge Institute for Medical Research, Hills Road, CB2 0XY, United Kingdom.
authors: Damian C
authors: DC
authors: Crowther
authors: Molecular Neurobiology Unit, Instituto de Biologia Molecular e Celular (IBMC), Rua do Campo Alegre 823, 4150-180 Porto, Portugal; Escola Superior de Tecnologia da Saúde do Porto, Instituto Politécnico do Porto, Rua Valente Perfeito 322, 4400-330 Vila Nova de Gaia, Portugal. Electronic address: icardoso@ibmc.up.pt.
authors: Isabel
authors: I
authors: Cardoso
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D052160:Benzothiazoles; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology*; D004331:Drosophila melanogaster; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D008136:Longevity / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D000900:Anti-Bacterial Agents; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D013844:Thiazoles; C009462:thioflavin T; D053148:Caspase 3; D004318:Doxycycline