Gene deletion of cystatin C aggravates brain damage following focal ischemia but mitigates the neuronal injury after global ischemia in the mouse

Neuroscience. 2004;128(1):65-71. doi: 10.1016/j.neuroscience.2004.06.024.

Abstract

Cystatin C is distributed in all human tissues and fluids with a particular abundance in the cerebrospinal fluid. Cystatin C is a strong endogenous inhibitor of lysosomal cysteine proteases, such as cathepsin B, L, H and S, that are involved in various biological processes such as degradation of cellular proteins and regulation of enzymes, as well as in pathological processes. Pharmacological inhibition of cathepsins has been shown to reduce neuronal damage after brain ischemia, suggesting that cystatin C is an endogenous neuroprotectant. Cystatin C has also amyloidogenic properties and is co-localized with beta-amyloid in degenerated neurons in Alzheimer's disease, suggesting a role in neuronal degeneration. To test the hypothesis that endogenous cystatin C is neuroprotective during brain ischemia, global and focal brain ischemia was induced in mice with the cystatin C gene knocked out. Following focal ischemia, larger brain infarcts were found in cystatin C knockout mice, probably due to a reduced inhibition of the cathepsins during ischemia. In contrast, brain damage after global ischemia was diminished in cystatin C knockout mice, suggesting that cystatin C has an aggravating effect on selective neuronal damage after global ischemia.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / blood supply
  • Brain / metabolism
  • Brain / pathology*
  • Brain Ischemia / genetics*
  • Brain Ischemia / pathology*
  • Cystatin C
  • Cystatins / genetics*
  • Enzyme-Linked Immunosorbent Assay
  • Gene Deletion
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Knockout
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Neurons / pathology

Substances

  • CST3 protein, human
  • Cst3 protein, mouse
  • Cystatin C
  • Cystatins