Co-involvement of mitochondria and endoplasmic reticulum in regulation of apoptosis: changes in cytochrome c, Bcl-2 and Bax in the hippocampus of aluminum-treated rabbits.
Neurodegenerative diseases, including Alzheimer's disease, are characterized by a progressive and selective loss of neurons. Apoptosis under mitochondrial control has been implicated in this neuronal death process, involving the release of cytochrome c into the cytoplasm and initiation of the apoptosis cascade. However, a growing body of evidence suggests an active role for the endoplasmic reticulum in regulating apoptosis, either independent of mitochondrial, or in concert with mitochondrial-initiated pathways. Members of the Bcl-2 family of proteins have been shown to either inhibit apoptosis, as is the case with Bcl-2, or to promote it, in the case of Bax. Investigations in our laboratory have focused on neuronal injury resulting from the intracisternal administration of aluminum maltolate to New Zealand white rabbits, an animal system relevant to a study of human disease in that it reflects many of the histological and biochemical changes associated with Alzheimer's disease. Here we report that treatment of young adult rabbits with aluminum maltolate induces both cytochrome c translocation into brain cytosol, and caspase-3 activation. Furthermore, as assessed by Western blot analysis, these effects are accompanied by a decrease in Bcl-2 and an increase in Bax reactivity in the endoplasmic reticulum.
Ghribi
O
O
Department of Pathology, University of Virginia Health Sciences Center, Box 168, Charlottesville, VA 22908, USA.
DeWitt
D A
DA
Forbes
M S
MS
Herman
M M
MM
Savory
J
J
D000535:Aluminum; D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007150:Immunohistochemistry; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism; D011817:Rabbits; D013347:Subcellular Fractions; D051028:bcl-2-Associated X Protein
D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000535:Aluminum; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases