Molecular Switch for the Brains's Fountain of Youth Found

A molecule that accumulates with age and inhibits the formation of new neurons can be switched off to completely reverse the negative effect, found researchers from the German Cancer Research Center (DKFZ) in Heidelberg. The discovery could allow scientists to design therapies to prevent age-related cognitive decline.

Key to the success in neuroscientist Prof. Dr. Ana Martin-Villalba and her teams search for the molecular causes for the decrease in new neuron production (neurogenesis), which is considered to be among the causes of declining memory and learning ability, was the Dickkopf-1 (Dkk1) protein which was found in the brains of aged mice.

"We find considerably more Dickkopf-1 protein in the brains of older mice than in those of young animals. We therefore suspected this signaling molecule to be responsible for the fact that hardly any young neurons are generated any more in old age," Martin-Villalba said. The scientists tested their assumption in mice whose Dickkopf-1 gene is permanently silenced. Professor Christof Niehrs had developed these animals at DKFZ, who had come across the substance when he found in 1998 that this signaling molecule regulates head development during embryogenesis. The term "Dickkopf" (from German "dick" = thick, "Kopf" = head) also goes back to Niehrs.

By blocking production of Dkk1, "we released a brake on neuronal birth, thereby resetting performance in spatial memory tasks back to levels observed in younger animals," says senior author Dr. Ana Martin-Villalba.

Aged mice that lacked Dkk1 performed just as well as young mice in memory and recognition tests because the ability of the neural stem cells in their brains to self-renew and generate immature neurons in the hippocampus (involved in memory) was restored to youthful levels.

The difference was particularly obvious in two-year old mice: In the knockout mice of this age, the researchers counted 80 percent more young neurons than in control animals of the same age. Moreover, the newly formed cells in the adult Dickkopf-1 mutant mice matured into potent neurons with multiple branches. In contrast, neurons in control animals of the same age were found to be more rudimentary already.

The investigators also found that young mice lacking Dkk1 were less susceptible to developing acute stress-induced depression than normal mice. This suggests that, in addition to slowing memory loss during aging, neutralizing Dkk1 (which is also present in human brains) could be beneficial in counteracting symptoms of depression.

The results give rise to the question whether the function of Dickkopf-1 may be turned off using drugs. Antibodies blocking the Dickkopf protein are actually already being tested in clinical trials for treating a completely different condition. "It is fascinating to speculate that such a substance may also slow down age-related cognitive decline," concludes Ana Martin-Villalba, who heads a research department at the DKFZ, which is the largest biomedical research institute in Germany with more than 2,500 employees.

Paper:

Désirée R.M. Seib, Nina S. Corsini, Kristina Ellwanger, Christian Plaas, Alvaro Mateos, Claudia Pitzer, Christof Niehrs, Tansu Celikel and Ana Martin-Villalba: Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline. Cell Stem Cell 2013, DOI: 10.1016/j.stem.2012.11.010