The goal of this study was to assess the in vivo effect of Aβ on apoptosis pathways involving the endoplasmic reticulum and mitochondria, and its relationship to the induction of tau phosphorylation and DNA oxidative damage. In rabbits treated intracisternally with aggregated Aβ(1-42), clear evidence of endoplasmic reticulum stress was observed by the activation of caspase-12 and cleavage of caspase-3 in the endoplasmic reticulum. Mitochondrial injury was evident from the release of cytochrome c into the cytosol and the induction of oxidized mitochondrial DNA. Tau phosphorylation and nuclear translocation of NF-κB and GSK-3β were also observed. Treatment with lithium, an inhibitor of GSK-3β, inhibited caspase activation but did not prevent mitochondrial DNA damage or tau hyperphosphorylation, suggesting that the translocation of GSK-3β may represent an up-stream event that leads to caspase activation but is unrelated to tau hyperphosphorylation or mitochondrial DNA oxidative damage. We propose that treatment by lithium alone is not sufficient to protect against the multiple adverse effects of Aβ, and the use of agents that prevent oxidative DNA damage and tau hyperphosphorylation, together with lithium, may provide better protection from the neurotoxic effect of Aβ.
- Caspase 12
- Caspase 3
- Cytochrome c
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience