title: Axonal protection via modulation of the amyloidogenic pathway in tumor necrosis factor-induced optic neuropathy.
abstract: OBJECTIVE
  To examine the changes in and localization of phosphorylated presenilin1 (p-PS1) and amyloid precursor protein (APP) in the optic nerve after intravitreal injection of TNF and to investigate the role of γ-secretase in the cleavage of APP in optic nerve degeneration.
  
  
  METHODS
  Groups of rats were euthanatized at 1 or 2 weeks after intravitreal injection of TNF. Levels of p-PS1 protein in the optic nerve were determined by immunoblotting and immunohistochemistry. The localization of APP was determined by immunohistochemistry, and its downstream cleavage was determined by immunoprecipitation using 6E10 antibody followed by immunoblotting with an APP intracellular domain (AICD) antibody. The effect of a γ-secretase inhibitor on TNF-induced optic nerve degeneration was determined by counting the number of axons.
  
  
  RESULTS
  p-PS1 was increased in the optic nerve after TNF injection and was found to colocalize with vimentin and glial fibrillary acidic protein, markers of astrocytes. Immunoprecipitation using 6E10 antibody followed by immunoblotting with AICD antibody revealed an increase in γ-secretase activation in the optic nerve after TNF injection, which was inhibited by treatment with the γ-secretase inhibitor. Moreover, γ-secretase inhibition significantly prevented the loss of axons in the optic nerve after TNF injection.
  
  
  CONCLUSIONS
  The increase in p-PS1 and activation of γ-secretase in the optic nerve may be associated with TNF-induced axonal degeneration. Modulation of γ-secretase activity may be useful for the treatment of TNF-related optic neuropathy.
authors.affiliation: Department of Ophthalmology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kojima
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kitaoka
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Munemasa
authors.forename: Satoki
authors.initials: S
authors.lastname: Ueno
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D009900:Optic Nerve / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009901:Optic Nerve Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects
chemical_list: D016564:Amyloid beta-Protein Precursor; D014409:Tumor Necrosis Factor-alpha