Lithium inhibits Abeta-induced stress in endoplasmic reticulum of rabbit hippocampus but does not prevent oxidative damage and tau phosphorylation.
The goal of this study was to assess the in vivo effect of Abeta 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 Abeta(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-kappaB and GSK-3beta were also observed. Treatment with lithium, an inhibitor of GSK-3beta, inhibited caspase activation but did not prevent mitochondrial DNA damage or tau hyperphosphorylation, suggesting that the translocation of GSK-3beta may represent an upstream 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 Abeta, 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 Abeta.
Ghribi
Othman
O
Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.
Herman
Mary M
MM
Savory
John
J
D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008094:Lithium / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D020169:Caspases