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P3‐049: Effects of rehabilitation training on the alteration in tau modification by photothrombus‐induced ischemic stroke
Author(s) -
Joa Kyung-Lim,
Kim Hak-Su,
Moon Sohee,
Kim Sujin,
Kang Ju-Hee
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.06.915
Subject(s) - stroke (engine) , rehabilitation , medicine , neuroprotection , ischemic stroke , motor cortex , cortex (anatomy) , vascular dementia , ischemia , physical medicine and rehabilitation , dementia , cardiology , neuroscience , disease , psychology , physical therapy , engineering , mechanical engineering , stimulation
critical branch-point, which dictates several outcomes: nitric oxide generation from nitric oxide synthases (NOS) or polyamine production from arginase (Arg1). Several reports show that nitration of tau impacts tau metabolism and increases aggregation, thus biasing one or more pathways may dictate tau fate. Depletion of arginine may also lead to increased autophagy through amino acid sensing. Methods:Utilizing gene therapy (adeno-associated virus), cellular, animal models of tauopathy (rTg4510 and PS19 mice), and recombinant protein experiments we tested each of these potential mechanisms: 1) decrease tau nitration (shifting arginine metabolism away from the NOS pathway); 2) arginine depletion (and activation of autophagy); and 3) polyamine production. Results: We find dysregulation of the polyamine pathway in tau transgenic mice. Our data indicates that Arg1 overexpression in mouse models of tauopathy reduces the many aspects of the tau phenotype including reduced phospho-tau and nitrated tau, reduced tangle pathology, reduced atrophy, reduced high molecular weight tau, reduced markers of inflammation, reduced inhibitors of autophagy, and reduced protein kinase activation. We find similar outcomes in cell lines overexpressing tau with parallel Arg1 manipulations. Importantly, we identified that higher-order polyamines at physiological concentrations directly block tau aggregation and facilitate tubulin polymerization but acetylated forms fail to mimic this affect. Conclusions: These data suggest arginine metabolism and the polyamine pathway as therapeutic targets that may arrest or slow the progression of the tau pathology in models of tauopathies.