| Increased levels of oxidative stress and disruption of cellular calcium homeostasis are believed to contribute to neuronal dysfunction and degeneration in many different age-related neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, Huntington's disease and stroke. For example, in Alzheimer's disease, accumulation of aggregation prone forms of amyloid b-peptide (Ab) results in membrane lipid peroxidation. Lipid peroxidation impairs the function of membrane ion motive ATPases and glucose and glutamate transporters by a mechanism involving covalent modification of the transport proteins by the aldehyde product of lipid peroxidation, 4-hydroxynonenal (HNE). Impairment of the membrane transporters promotes membrane depolarization and calcium influx through glutamate receptor channels and voltage-dependent calcium channels. In addition, subtoxic levels of membrane lipid peroxidation impair function of signal transduction pathways for neurotransmitters and growth factors. For example, coupling of muscarinic acetylcholine receptors and metabotropic glutamate receptors to the GTP binding protein GQ11 perturbs signaling by these neurotransmitters. Increases in intracellular calcium levels promotes oxidative stress by several mechanisms. For example, increased cytoplasmic calcium levels disturb mitochondrial function leading to increased production of superoxide anion radical. Superoxide is converted by superoxide dismutases to hydrogen peroxide. Normally, hydrogen peroxide is eliminated from cells via the action of catalase and glutathione peroxidase. However, under conditions of elevated calcium levels and excessive hydrogen peroxide production, and particularly in the presence of trace metals such as Fe2+, hydrogen peroxide is converted to the hydroxyl radical, a potent inducer of membrane lipid peroxidation. Calcium can also promote free radical production by activating the enzyme nitric oxide synthase (NOS) leading to the production of nitric oxide, a free radical that can interact with superoxide to form the toxic compound peroxynitrite. A final example is that calcium can activate the phospholipase A-2 pathway, leading to the production of arachidonic acid, which is then acted on by lipoxygenase and cyclooxygenases, again generating free radicals. The relative contributions of these different pathways for increased oxidative stress and perturbed calcium homeostasis may differ among age-related neurodegenerative conditions. However, these cascades appear to contribute to both apoptosis and excitotoxicity of neurons in many different age-related neurodegenerative disorders. |
