Phillip F Giannopoulos1, Jin Chu1, Margaret Sperow2, Jian-Guo Li1, W Haung Yu3, Lynn G Kirby4, Mary Abood4, Domenico Praticò5. 1. Center for Translational Medicine; Department of Pharmacology. 2. Center for Substance Abuse Research. 3. Taub Institute for Alzheimer's Disease Research, Department of Pathology and Cell Biology, Columbia University, New York, New York. 4. Center for Substance Abuse Research; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania. 5. Center for Translational Medicine; Department of Pharmacology. Electronic address: praticod@temple.edu.
Abstract
BACKGROUND: 5-Lipoxygenase (5-LO) is a protein widely distributed in the central nervous system where it modulates amyloidosis and memory impairments in transgenic mouse models of Alzheimer's disease. However, no data are available as to whether 5-LO is elevated in human tauopathy or if it directly influences tau pathology in a relevant model of the disease. METHODS: We assayed 5-LO levels in brain samples from patients with tauopathy and transgenic tau mice, and we evaluated the effect of 5-LO pharmacologic inhibition on the phenotype of these mice. RESULTS: The 5-LO protein is upregulated in human tauopathy and transgenic tau mice brains. Pharmacologic blockade of 5-LO in tau mice resulted in significant memory improvement, rescue of synaptic integrity and dysfunction, and reduction of tau pathology via a cdk5-dependent mechanism. CONCLUSIONS: These results establish a key role of 5-LO in the development of the tau pathology phenotype and demonstrate it to be a novel viable therapeutic target for the pharmacologic treatment of human tauopathy.
BACKGROUND:5-Lipoxygenase (5-LO) is a protein widely distributed in the central nervous system where it modulates amyloidosis and memory impairments in transgenicmouse models of Alzheimer's disease. However, no data are available as to whether 5-LO is elevated in humantauopathy or if it directly influences tau pathology in a relevant model of the disease. METHODS: We assayed 5-LO levels in brain samples from patients with tauopathy and transgenictaumice, and we evaluated the effect of 5-LO pharmacologic inhibition on the phenotype of these mice. RESULTS: The 5-LO protein is upregulated in humantauopathy and transgenictaumice brains. Pharmacologic blockade of 5-LO in taumice resulted in significant memory improvement, rescue of synaptic integrity and dysfunction, and reduction of tau pathology via a cdk5-dependent mechanism. CONCLUSIONS: These results establish a key role of 5-LO in the development of the tau pathology phenotype and demonstrate it to be a novel viable therapeutic target for the pharmacologic treatment of humantauopathy.
Authors: Haley C Dunn; Rahasson R Ager; David Baglietto-Vargas; David Cheng; Masashi Kitazawa; David H Cribbs; Rodrigo Medeiros Journal: J Alzheimers Dis Date: 2015 Impact factor: 4.472
Authors: K Duff; H Knight; L M Refolo; S Sanders; X Yu; M Picciano; B Malester; M Hutton; J Adamson; M Goedert; K Burki; P Davies Journal: Neurobiol Dis Date: 2000-04 Impact factor: 5.996