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Advisor(s)
Abstract(s)
Therapies for Alzheimer disease that reduce the production of pathogenic amyloid beta (A beta) 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 A beta toxicity and sought to correlate any effects with the aggregation state of the peptide. We found that administration of doxycycline to A beta 42-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 A beta 42 and showed that doxycycline administration partially rescued the toxicity of A beta 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 A beta fibrillization and favors the generation of smaller, non-amyloid structures that were nontoxic as determined by the lack of caspase 3 activation in a neuroblastoma cell line. Our confirmation that doxycycline can prevent amyloid beta toxicity both in vitro and in vivo supports its therapeutic potential in AD.
Description
Keywords
Amyloid beta-peptide Parkinsons-disease Mouse model A-beta Huntingtons-disease Lateral-sclerosis Rat model In-vitro Minocycline Tetracyclines
Citation
Costa, R., Speretta, E., Crowther, D. C., & Cardoso, I. (2011). Testing the therapeutic potential of doxycycline in a Drosophila melanogaster model of Alzheimer Disease*. Journal of Biological Chemistry, 286(48), 41647-41655. https://doi.org/https://doi.org/10.1074/jbc.M111.274548
Publisher
JBC Papers in Press