Tau and Oxidative Stress
Mouse models also have given researchers new tools to study the relationship between tau and the oxidative stress that results when dysfunctional mitochondria produce too many reactive oxygen species. The conference saw some fruits of this work. Mitochondrial dysfunction has become a point of convergence among many age-related neurodegenerative diseases, and researchers generally assume it to be one of the environmental risk factors that can spur the expression of the neurodegenerative disease for which a person is already at risk. Yet it is still unclear whether it is a primary or secondary event and how it intersects with the disease-specific pathogenic pathways.

In one talk, Ashley Bush of the Mental Health Research Institute, Victoria, Australia, and Massachusetts General Hospital in Charlestown, collaborating with Simon Melov’s lab at the Buck Institute in Novato, California, took advantage of an unusual mouse model to address the question. He used superoxide dismutase 2 (SOD2) knockout mice, whose lack of this radical-scavenging enzyme kills them soon after birth as the radical load overwhelms their peripheral tissues. By treating these mice with catalytic antioxidants, the scientists kept them alive long enough to be able to unmask their brain pathology. When studying their brains at 3 weeks of age, the scientists discovered massive increases in phosphorylation on three tau phosphorylation sites in AD-relevant areas. Increased doses of the antioxidant treatment ameliorated this effect. When the researchers halved the amount of genetically available SOD2 by crossing Tg2576 APP transgenics with heterozygous SOD2 knockouts (who survive and can reproduce), they saw the amyloid burden shoot up, as well. The increase in amyloid was blocked by the antioxidant they administered. The mice also showed changes in metal levels. The lab is now pursuing the relationship among iron, zinc, and phosphorylated tau in more detail.

The data available so far suggest that oxidative stress is a common upstream modulator of both amyloid and tau pathology, Bush noted. For their part, researchers led by Jada Lewis at the Mayo Clinic, Jacksonville, Florida, looked at markers of oxidative stress, such as heme oxygenase-1 and other genes induced in response to it, in their mice expressing the human P301L tau mutant that leads to FTDP-17.

Such work strengthens the case for antioxidative therapies and should lead to better treatments in this area. Many people currently take antioxidant supplements such as vitamin E, beta-carotine, or Ginkgo biloba (Christen, 2004) based on epidemiologic and other data. However, controlled trials of these compounds have mostly been disappointing so far, (e.g., Petersen et al., 2005). Delivering effective doses to the brain has been a major challenge.

Finally, a fresh approach to testing such compounds is worth including in this context, even though it does not offer data on tau yet. Monica Garcia-Alloza in Hyman’s group presented data from her study using the oxidation-sensitive reporter dye Amplex Red in multiphoton microscopy of APP transgenic mice. Working with Brian Bacskai, she found that applying vitamin E or Ginkgo biloba extract (though not beta-carotene) directly to the brain of Tg2576 mice, as well as feeding it orally for 15 days, reduced oxidative stress around plaques. Along with this reduction, she noticed that some curved dendrites were straightening out, similar to what this group had previously described for other experimental therapeutic interventions (Brendza et al., 2005). This suggests that antioxidant therapy might be useful for the structural damage seen with Alzheimer pathology.

The SfN conference had more to offer on tau. The Alzforum will be pleased to post readers' observations and additions as comments to this series.—Gabrielle Strobel.