Axonal Protection via Modulation of the Amyloidogenic Pathway in Tumor Necrosis Factor–Induced Optic Neuropathy

Abstract

PURPOSE.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 c-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 c-secretase inhibitor on TNFinduced 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 c-secretase activation in the optic nerve after TNF injection, which was inhibited by treatment with the c-secretase inhibitor. Moreover, c-secretase inhibition significantly prevented the loss of axons in the optic nerve after TNF injection.CONCLUSIONS. The increase in p-PS1 and activation of c-secretase in the optic nerve may be associated with TNF-induced axonal degeneration. Modulation of c-secretase activity may be useful for the treatment of TNF-related optic neuropathy. (Invest Ophthalmol Vis Sci. 2012;53:7675-7683)

Axonal protection by short-term hyperglycemia with involvement of autophagy in TNF-induced optic nerve degeneration

“…It is also interesting to note that a recent study has demonstrated that glucose rescued cultured rat retinal cells from rotenone-induced toxicity via both the pentose phosphate pathway and the glycolytic pathway, with the maintenance of ATP levels and reduced reactive oxygen species production (Han et al, 2013 ). On the other hand, we previously found that astrocytes in the optic nerve were activated after TNF injection (Kojima et al, 2012 ). Therefore, one hypothesis is that TNF enhances glucose utilization by astrocytes and can perturb their energy metabolism (Yu et al, 1995 ), thereby impairing the ability to provide adequate energy for axons.…”

Axonal Protection by Tacrolimus with Inhibition of NFATc1 in TNF-Induced Optic Nerve Degeneration

“…Increased expression of GFAP induced by TNF tended to be suppressed by tacrolimus. Intravitreal injection of TNF may lead to activation of microglia and astrocytes in optic nerve [ 18 , 33 ]. Therefore, it is reasonable to speculate that tacrolimus suppresses the activation of glial cells and inhibits the positive feedback loop among activated glia, cytokines and CaN/NFAT [ 34 ].…”

Histone H2B induces retinal ganglion cell death through toll-like receptor 4 in the vitreous of acute primary angle closure patients

“…One day after the intravitreal injection of H2B, membrane proteins were extracted from retinal cell lysis with a subcellular proteome extraction kit (Calbiochem, Darmastadt, Germany) according to the manufacturer's instructions. Immunoprecipitation was carried out with the Immunoprecipitation Starter Pack (GE Healthcare Bio-Sciences AB, Uppsala, Sweden), as described previously [22]. The supernatants were incubated with a TLR4 antibody (Santa Cruz Biotechnology, Santa Cruz, CA).…”