There is growing evidence that oxidative stress is an important factor in Alzheimer's disease.  Alzheimer's patients show an increase in oxidized DNA, proteins, and fatty acids in affected brain regions.  These oxidative changes can arise from the normal aging process, head trauma, increased levels of heavy metals (iron, aluminum, and mercury), and possibly the aggregation of the ß-amyloid protein (Aß).

We have attempted to model oxidative stress in our polymerization assay using agents that protect tau from oxidation, a general anti-oxidant, and an oxidizing system that consisted mainly of iron.  We found that the oxidation of the tau molecule itself does not enhance its polymerization, but rather the oxidation of the fatty acids that we use to induce polymerization enhanced the process (see Gamblin et. al., 2000 for details).

This result might be very interesting since Alzheimer's patients show an increase in the amount of fatty acid oxidation products in their urine, cerebrospinal fluid, and brain regions that are afflicted with Alzheimer's pathology.  In addition, existing putative protective factors for AD include antioxidant vitamins and nonsteroidal anti-inflammatory drugs that target the pathways of oxidative stress and fatty acid metabolism.  These factors presumably ameliorate the excessive non-enzymatic lipid peroxidation and cyclooxygenase lipid processing associated with AD.

Therefore, we propose a model for tau's involvement in the oxidative stress pathway in Alzheimer's Disease:

Figure 7 from Gamblin et. al., 2000

In this model, reactive oxygen species that result from normal aging or possibly Aß polymerization attack the plama membrane and oxidize fatty acids that are released into the cytoplasm.  These fatty acid metabolites would then induce tau to form filaments that would directly lead to neuronal dysfunction and eventual cell death.  Although the actual mechanisms for this process would be much more complicated than what we have depicted here, we use this model as a reminder of the processes that we are interested in investigating.

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