Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer's disease.

Autor: Xu J; Child Study Center, Yale University, New Haven, Connecticut, United States of America., Chatterjee M; Child Study Center, Yale University, New Haven, Connecticut, United States of America., Baguley TD; Department of Chemistry, Yale University, New Haven, Connecticut, United States of America., Brouillette J; Child Study Center, Yale University, New Haven, Connecticut, United States of America., Kurup P; Child Study Center, Yale University, New Haven, Connecticut, United States of America., Ghosh D; Child Study Center, Yale University, New Haven, Connecticut, United States of America., Kanyo J; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America., Zhang Y; Child Study Center, Yale University, New Haven, Connecticut, United States of America; Laboratory for Drug Discovery in Neurodegeneration and Department of Neurology, Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America., Seyb K; Laboratory for Drug Discovery in Neurodegeneration and Department of Neurology, Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America., Ononenyi C; Child Study Center, Yale University, New Haven, Connecticut, United States of America., Foscue E; Child Study Center, Yale University, New Haven, Connecticut, United States of America., Anderson GM; Child Study Center, Yale University, New Haven, Connecticut, United States of America; Department of Laboratory Medicine, Yale University, New Haven, Connecticut, United States of America., Gresack J; Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, United States of America., Cuny GD; Laboratory for Drug Discovery in Neurodegeneration and Department of Neurology, Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America., Glicksman MA; Laboratory for Drug Discovery in Neurodegeneration and Department of Neurology, Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America., Greengard P; Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, United States of America., Lam TT; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America., Tautz L; Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America., Nairn AC; Department of Psychiatry, Yale University, New Haven, Connecticut, United States of America., Ellman JA; Department of Chemistry, Yale University, New Haven, Connecticut, United States of America., Lombroso PJ; Child Study Center, Yale University, New Haven, Connecticut, United States of America; Department of Psychiatry, Yale University, New Haven, Connecticut, United States of America; Department of Neurobiology, Yale University, New Haven, Connecticut, United States of America.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2014 Aug 05; Vol. 12 (8), pp. e1001923. Date of Electronic Publication: 2014 Aug 05 (Print Publication: 2014).
DOI: 10.1371/journal.pbio.1001923
Abstrakt: STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels.
Competing Interests: The authors declare that they have no competing interests.
Databáze: MEDLINE
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