Dale E. Bredesen, M.D., Professor

Programmed cell death: mechanisms and implications

The Bredesen laboratory focuses on the biochemical mechanisms that control cell death. Virtually all cells contain a set of internal suicide programs — cell suicide is a vital mechanism for development and maintenance in humans, and the loss of the tight regulation of cell death can result in a wide variety of diseases. Cancer develops when cells fail to commit suicide and continue to grow and survive, but too much cell death can also be harmful, such as occurs with neurodegenerative diseases like Alzheimer’s.

In 2006, the Bredesen lab published a study in the Proceedings of the National Academies of Sciences providing a startling new look at Alzheimer’s disease (AD), and in 2007 the laboratory submitted key follow-up studies for publication. There are over 200 mice at the Buck Institute that should have the symptoms of AD. But these mice, despite the fact that their brains are replete with beta-amyloid tangles (the sticky deposits commonly associated with Alzheimer’s disease), have normal memories, and show no signs of the brain shrinkage and neuron damage commonly associated with AD. This research has provided both new drug targets for AD, as well as a completely new understanding of the disease itself.

In addition, these studies have produced an important new “tool” for research: for the first time, there are genetically matched mice in two groups, both of which display the upstream part of AD (senile plaques and Abeta accumulation) but only one of which displays the various symptoms of the disease, such as loss of brain cell connections and the associated loss of memory. This is an important tool because any biochemical pathway can now be compared in these two groups.

The lab is studying one particular biochemical pathway involving a regulatory enzyme that is markedly abnormal very early in the mouse model of AD (and is also abnormal in human patients), yet is completely normal in the mice in which the symptoms of AD has been prevented. This will now allow the laboratory to use a drug to block aspects of this pathway in both groups of mice, to determine whether this alters the development of AD.