Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension.

Published

Journal Article

PURPOSE: Retinal ganglion cell (RGC) death in glaucoma involves apoptosis. Activation of caspases and abnormal processing of amyloid precursor protein (APP) are important events in other chronic neurodegenerations, such as Alzheimer's disease (AD). The retinal expression and activation of caspases and the patterns of caspase-3-mediated APP processing in ocular hypertensive models of rat glaucoma were investigated. METHODS: RGC death was produced in one eye by chronic exposure to increased intraocular pressure (IOP) or by optic nerve transection. Elevated IOP was produced by obstruction of aqueous humor outflow with laser coagulation or limbal hypertonic saline injection. Caspase activity and APP processing in the retina were examined by RNase protection assay (RPA), immunocytochemistry, immunoblot assay, and colorimetric assay. RESULTS: RPA revealed elevations of caspase-3 mRNA, as well as other apoptosis-related mRNAs. Immunocytochemistry showed caspase-3 activation in RGCs damaged by ocular hypertension. The generation of the caspase-3-mediated APP cleavage product (DeltaC-APP) was also increased in ocular hypertensive RGCs. Western immunoblot assay and colorimetry revealed significantly more activated caspase-3 in ocular hypertensive retinas than in control retinas. The activated form of caspase-8, an initiator caspase, and amyloid-beta, a product of APP proteolysis and a component of senile plaques in AD, were detected in RGCs by immunohistochemistry significantly more often in ocular hypertensive than in control retinas. The amounts of full-length APP were reduced and amyloid-beta-containing fragments were increased in ocular hypertensive retinas by Western immunoblot assay. CONCLUSIONS: Rat RGCs subjected to chronic ocular hypertension demonstrate caspase activation and abnormal processing of APP, which may contribute to the pathophysiology of glaucoma.

Full Text

Duke Authors

Cited Authors

  • McKinnon, SJ; Lehman, DM; Kerrigan-Baumrind, LA; Merges, CA; Pease, ME; Kerrigan, DF; Ransom, NL; Tahzib, NG; Reitsamer, HA; Levkovitch-Verbin, H; Quigley, HA; Zack, DJ

Published Date

  • April 2002

Published In

Volume / Issue

  • 43 / 4

Start / End Page

  • 1077 - 1087

PubMed ID

  • 11923249

Pubmed Central ID

  • 11923249

International Standard Serial Number (ISSN)

  • 0146-0404

Language

  • eng

Conference Location

  • United States