Anti-apoptotic signaling and failure of apoptosis in the ischemic rat hippocampus.
Several anti-apoptotic proteins are induced in CA1 neurons after transient forebrain ischemia (TFI), but fail to protect the majority of these cells from demise. Correlating cell death morphologies (apoptosis-like and necrosis-like death) with immunohistochemistry (IHC), we investigated whether anti-apoptosis contributes to survival, compromises apoptosis effector functions and/or delays death in CA1 neurons 1-7 days after TFI. As surrogate markers for bioenergetic failure, the IHC of respiratory chain complex (RCC) subunits was investigated. Dentate granule cell (DGC) apoptosis following colchicine injection severed as a reference for classical apoptosis. Heat shock protein 70 (Hsp70), neuronal apoptosis inhibitory protein (NAIP) and manganese superoxide dismutase (MnSOD) were upregulated in the majority of intact CA1 neurons paralleling the occurrence of CA1 neuronal death (days 3-7) as well as in a proportion of apoptosis-(<50%) and necrosis-like (<30%) CA1 neurons. Colchicine did not provoke an anti-apoptotic response in DGC at all. In addition, more than 70% of apoptosis- and necrosis-like CA1 neurons had completely lost their RCC subunits suggesting bioenergetic failure; by contrast, following colchicine injection, 88% of all apoptotic DGC presented RCC subunits. Thus, anti-apoptotic proteins may, in a subset of ischemic CA1 neurons, prevent cell death, while in others, affected by pronounced energy failure, they may cause secondary necrosis.
Müller
Georg Johannes
GJ
Molecular Neuropathology Group, University of Copenhagen, 11, Frederik V's vej, 2100-Copenhagen-O, Denmark.
Lassmann
Hans
H
Johansen
Flemming Fryd
FF
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D003078:Colchicine / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology*; D042967:Electron Transport Complex I / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases; D009336:Necrosis; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology
D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; C496803:Naip6 protein, rat; D051616:Neuronal Apoptosis-Inhibitory Protein; D051996:Transcription Factor RelA; D050257:Tubulin Modulators; D013482:Superoxide Dismutase; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; D042967:Electron Transport Complex I; C020439:oligomycin sensitivity-conferring protein; D003078:Colchicine