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P4‐259: PHOSPHODIESTERASE 5 (PDE5) AS A POTENTIAL THERAPEUTIC TARGET IN SMALL ARTERIES OF AGED HUMAN BRAINS
Author(s) -
Hainsworth Atticus H.,
Vasita Ekta,
Andoh Joycelyn,
Esiri Margaret M.
Publication year - 2014
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.2014.07.030
Subject(s) - medicine , sildenafil , vasodilation , cgmp specific phosphodiesterase type 5 , pathology , white matter , cardiology , magnetic resonance imaging , radiology
pSer-Pro sequences, implicates prolyl isomerization in misfolding of hyperphosphorylated tau. Methods: The structural effects of phosphorylation versus O-GlcNAcylation were examined in the tau proline-rich domain and in the C-terminal domain by circular dichroism and heteronuclear NMR spectroscopy via examination of non-phosphorylated, phosphorylated, and O-GlcNAcylated peptides comprising tau174-251 and tau395411. Peptides were also examined with the R406W mutation in both non-phosphorylated and phosphorylated forms. Results: Phosphorylation was found to induce a strong disorder-to-order transition in the prolinerich domain, with special ordering observed on the residues pT175, pT181, pT212, pT217, and pT231. Phosphothreonine adopts a stable, ordered structure with a strong hydrogen bond to its own amide. O-GlcNAcylation opposed this structural change. We hypothesized that mutation of R406 to tryptophan (R406W) would lead to increased cis amide bond. R406W tau peptides exhibited increased population of cis amide bond, due to a favorable H a -cis-Pro-aromatic C-H/p interaction. Phosphorylation of Ser404 further increased the population of cis-proline at pSer404-Pro405, with greatest effect in R406W. Conclusions: These data suggest a disorderto-order transition uponphosphorylation in the proline-rich domain as a basis for changes in the dynamic structure of tau. R406W mutation results in higher populations of cis amide bond. Phosphorylation of Ser404 leads to further increases in population of cis amide bond, particularly in R406W. Cis amide bond prevents phosphatase activity, and therefore tau-R406W induces both greater structural changes and longer phosphorylation residence times.