Common Enzyme Sheds Light on Health and Disease

Developmental Cell, March 13, 2009

Researchers at the Washington University School of Medicine in St. Louis report some interesting discoveries with the enzyme known as adenosine monophosphate-activated protein kinase (AMPK). Already known to be involved in a number of diseases, AMPK has been well studied by scientists for many years, but these new findings are the first of their kind to demonstrate that the enzyme is essential for the health of neural stem cells.

In a study led by Jeffrey Milbrandt, M.D., Ph.D., the researchers found that when they selectively deactivated the enzyme in mouse embryos, the overall brain size of each mouse shrunk by 50%, with dramatic shrinkage in both the cerebrum and the cerebellum to such an extent that the mice died within 3 weeks of birth. AMPK, it turns out, is a critical component for the survival of neural stem cells which in turn create and maintain the cells of the central nervous system, including the cells that are necessary for learning and memory. When AMPK is deactivated or absent altogether, normal neurological health cannot be maintained at the cellular level.

According to Dr. Milbrandt, "For years, scientists have shown how AMPK regulates multiple metabolic processes, and revealed how that influence can affect cancer, diabetes, and many other diseases. Now, for the first time, we've shown that AMPK can cause lasting changes in cell development. That's very exciting because it opens the possibility of modifying AMPK activity to improve brain function and health."

AMPK is directly involved in the regulation of cellular energy usage, and the enzyme is specifically activated whenever energy resources are low, such as during times of caloric restriction or sustained physical exercise. When activated, AMPK promotes cellular glucose uptake, mitochondria formation, fatty acid oxidation and other energy-producing cellular processes, while simultaneously inhibiting protein and fatty acid synthesis as well as cell reproduction and other energy-consuming cellular processes.

When activated, there is one particular version of AMPK that is capable of making its way into the nucleus of cells where it inactivates the retinoblastoma protein, "a master regulator" of cell production, which in turn allows neural stem cells to survive and proliferate. That particular version of AMPK, which contains the beta 1 subunit and which is only one of several versions of AMPK, is capable of penetrating both the cytoplasm and the nucleus of cells, whereas other versions, such as that which contains the beta 2 subunit, have only been found in the cytoplasm but never in the cell nucleus. As Dr. Biplab Dasgupta, a lead author of the paper, describes, "Inhibiting AMPK is something that most cells don't like. It can lead to a variety of consequences, including cell death, but many cell types can tolerate it. In contrast, neural stem cells undergo catastrophic cell death in the absence of AMPK containing the beta 1 subunit. We also suspect loss of this form of AMPK may cause severe problems for other stem cells."

Because of the role of cancer stem cells in some types of cancer, and the possibility of manipulating AMPK in cancer therapies, ideally the trick would be to inactivate AMPK in the cancer stem cells themselves, while simultaneously activating AMPK in the normal, non-cancerous cells.

Since the protein retinoblastoma, which the AMPK version with the beta 1 subunit regulates in the cell nucleus, plays such an important role in the differentiation of stem cells, these findings also have possible implications for the long-term health effects of malnutrion. According to a study that was conducted in 1977 on the children of women who were starved by the Nazis during World War II, these children remained at a high risk of various diseases throughout their lives, which included diabetes, heart disease and stroke. Even though these children, themselves, had never been subjected to starvation, their mothers may have incurred long-term damage to their stem cells as a result of their experiences, which in turn influenced the cellular health and development of their offspring.

On a lighter note, Dr. Dasgupta adds, "Exercise activates AMPK and improves cognitive function. Our results suggest brain function may improve because additional activated AMPK makes it easier for adult neural stem cells to reproduce and become new brain cells."

As Dr. Milbrandt concludes, "Manipulating this regulation may enable us to encourage the development of new brain cells. We might use that not only to treat medical conditions where brain development is hampered, but also to improve cognitive function generally."