Intracellular mechanisms underlying aluminum-induced apoptosis in rabbit brain.
Loss of neurons is a hallmark of neurodegenerative disorders and there is increasing evidence suggesting that apoptosis is a key mechanism by which neurons die in these diseases. Mitochondrial dysfunction has been implicated in this process of neuronal cell death, but there is a growing body of evidence suggesting also an active role for the endoplasmic reticulum in regulating apoptosis, either independent of mitochondria, or in concert with mitochondrial-initiated pathways. Investigations in our laboratory have focused on neuronal injury resulting from the administration of aluminum maltolate, via the intracisternal route, to New Zealand white rabbits. This treatment induces both mitochondrial and endoplasmic reticulum stress. Agents such as lithium or glial cell-line derived neurotrophic factor (GDNF) have the ability to prevent aluminum-induced neuronal death by interfering with the mitochondrial and/or the endoplasmic reticulum-mediated apoptosis cascade. Cytochrome c release from mitochondria and binding to Apaf-1 initiates the aluminum-induced apoptosis cascade; this is prevented by lithium treatment. GDNF also protects against aluminum-induced apoptosis but by upregulation of Bcl-X(L), thereby preventing the binding of cytochrome c to Apaf-1. This animal model system involving neurotoxicity induced by an aluminum compound provides new information on mechanisms of neurodegeneration and neuroprotection.
D000535:Aluminum / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011817:Rabbits; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; D045304:Cytochromes c; D000535:Aluminum; D020169:Caspases