Role of hydrogen peroxide in the aetiology of Alzheimer's disease: implications for treatment

Hydrogen peroxide (H₂O₂) is a stable, uncharged and freely diffusable reactive oxygen species (ROS) and second messenger. The generation of H₂O₂ in the brain is relatively high because of the high oxygen consumption in the tissue. Alzheimer's disease is a neurodegenerative disorder characterised by the appearance of amyloid-β (Aβ)-containing plaques and hyperphosphorylated tau-containing neurofibrillary tangles. The pathology of Alzheimer's disease is also associated with oxidative stress and H₂O₂ is implicated in this and the neurotoxicity of the Aβ peptide. The ability for Aβ to generate H₂O₂, and interactions of H₂O ₂ with iron and copper to generate highly toxic ROS, may provide a mechanism for the oxidative stress associated with Alzheimer's disease. The role of heavy metals in Alzheimer's disease pathology and the toxicity of the H₂O₂ molecule may be closely linked. Drugs that prevent oxidative stress include antioxidants, modifiers of the enzymes involved in ROS generation and metabolism, metal chelating agents and agents that can remove the stimulus for ROS generation. In Alzheimer's disease the H₂O ₂ molecule must be considered a therapeutic target for treatment of the oxidative stress associated with the disease. The actions of H ₂O₂ include modifications of proteins, lipids and DNA, all of which are effects seen in the Alzheimer's disease brain and may contribute to the loss of synaptic function characteristic of the disease. The effectiveness of drugs to target this component of the disease pathology remains to be determined; however, metal chelators may provide an effective route and have the added bonus in the case of clioquinol of potentially reducing the Aβ load. Future research and development of agents that specifically target the H₂O₂ molecule or enzymes involved in its metabolism may provide the future route to Alzheimer's disease therapy.