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 characterize d by a progressive and selective loss of neurons. Apoptosis under mitochond rial control has been implicated in this neuronal death process, involving the release of cytochrome c into the cytoplasm and initiation of the apopto sis cascade. However. a growing body of evidence suggests an active role fo r 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 apoptosi s, as is the case with Bcl-2, or to promote it, in the case of Bax. Investi gations in our laboratory have focused on neuronal injury resulting from th e intracisternal administration of aluminum maltolate to New Zealand white rabbits, an animal system relevant to a study of human disease in that it r eflects many of the histological and biochemical changes associated with Al zheimer'.s disease. Here we report that treatment of young adult rabbits wi th aluminum maltolate induces both cytochrome c translocation into brain cy tosol, and caspase-3 activation. Furthermore. as assessed by Western blot a nalysis, these effects are accompanied by a decrease in Bcl-2 and an increa se in Bax reactivity in the endoplasmic reticulum. (C) 2001 Elsevier Scienc e B.V. All rights reserved.