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Evaluation of clinically-approved drugs to target tau toxicity in zebrafish model

Grant number: 15/03507-4
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): June 15, 2015
Effective date (End): June 14, 2016
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Soraya Soubhi Smaili
Grantee:Rodrigo Portes Ureshino
Supervisor abroad: David Chaim Rubinsztein
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Local de pesquisa : University of Cambridge, England  
Associated to the scholarship:12/08273-3 - Study of autophagy and neuroprotection in aging and in a Parkinson's Disease animal model, BP.PD

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. The neurobiological hallmarks of AD consist of extracellular amyloid plaques and intracellular neurofibrillary tangles, which are mainly formed by hyperphosphorylated tau. This hallmark strongly correlates with dementia and is therefore an interesting potential target for small molecules to modulate tau toxicity. Previous results show that small molecule autophagy enhancers such as rapamycin ameliorated the degeneration observed in the zebrafish tau model. Here we propose to perform a screen for clinically-approved drugs that can reduce tau toxicity. For this we will use zebrafish models expressing human wild-type tau or P301L tau, which develop progressive tau accumulation, tau phosphorylation, and photoreceptor death. At first, we will perform a primary screen to identify compounds that are able to restore GFP levels from EGFP-tagged human tau photoreceptors, lost due tau toxicity, following by the quantification of the numbers of photoreceptors using fluorescent image analysis. We will also perform concentration response analysis. Finally, if time permits, we will establish the mechanisms of tau clearance (proteasomal or autophagic activity), (de)phosphorylation as well as cell death, investigated by western blotting and immunohistochemistry. The screening for novel strategies and specific autophagy-target drugs in the pursuit of minimizing aggregate-prone proteins accumulation such as tau can ameliorate cell toxicity in degenerative diseases. (AU)