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Dickkopf deficiency improves cognitive performance

Scientists from the German Cancer Research Center have shown that the Dickkopf gene, which regulates head development during embryogenesis, prevents the regeneration of nerve cells in the mouse hippocampus. This also leads to the loss of learning capacity in advanced age. Animals in advanced adult age whose Dickkopf gene had been silenced showed no age-related decline in cognitive performance.

“DKFZ researchers find the cause of age-related cognitive decline.” The headline in the press release of the German Cancer Research Center (DKFZ) of 8th February 2013 certainly arouses our curiosity. However, for the time being the discovery only concerns research carried out on mice; a recipe for keeping mental agility in old age is still a pipe dream.

Neural stem cells and their effectors

Professor Dr. Ana Martin-Villalba, Molecular Neurobiology, German Cancer Research Center © DKFZ

The hippocampus, a seahorse-shaped structure of the brain, is the site of cognitive abilities such as spatial orientation and where short-term memories are transformed into long-term memories. The scientists have shown in mice that hippocampus performance depends on two processes associated with cognitive decline in old age: synaptogenesis and neurogenesis. Synaptogenesis is the formation of synapses between neurons in the nervous system. Synaptic consolidation resulting from frequent use leads to the storage of long-lasting memories in the cerebrum by way of interneurons. Synapses that are less frequently used are weaker and degrade, as the cells only survive when they communicate with each other. In addition to this process, which is referred to as synaptic plasticity, neurons can also develop de novo from neural stem cells or neural progenitor cells (NPCs). In the adult brain, continuous neurogenesis is restricted to certain brain areas, i.e. the hippocampus and the subventricular zone of the lateral ventricles. NPCs play a key role in neurological disease and brain repair; however, the hyperactivation of these cells can lead to the development of tumours.

Location of the hippocampus in the human brain © IZN, Universität Heidelberg

“In old age, the production of new neurons dramatically decreases. This is considered to be among the causes of declining memory and learning ability,” explains Prof. Dr. Ana Martin-Villalba, a neuroscientist at the DFKZ in Heidelberg. Martin-Villalba and her team in the Department of Molecular Neurobiology at the DKFZ are trying to find the molecular causes for the decrease in new neuron production (neurogenesis) in the hippocampus. Specific molecules in the immediate environment of stem cells determine the fate of NPCs: they may remain dormant, renew themselves or differentiate into one of two types of specialized brain cells, astrocytes or neurons. 

One of these factors is the death receptor CD95, whose role in activating adult neural stem cells for working memory formation and brain repair was identified by Martin-Villalba and her team in 2009. In 1989, Prof. Dr. Peter Krammer and co-workers had discovered the CD95 system, its signalling machinery and its role in apoptosis (programmed cell death). CD95 has different functions in different cells. In healthy brains or brains damaged as a result of anaemia, CD95 plays a crucial role in the survival of stem cells and their differentiation into different cell lineages. In glioblastoma cells (ed. note: glioblastoma is a very aggressive brain tumour), CD95 stimulates the migration and invasion of tumour cells. The activity of the stem cells is controlled by the Wnt/β-catenin signalling pathway, which also plays a key role in brain development and other developmental processes during embryogenesis. The Wnt genes encode secretory lipoproteins which bind to a transmembrane receptor and induce a signalling cascade that promotes the formation of new neurons. The researchers from Heidelberg have now discovered a molecular counterpart, called Dickkopf-1 (DKK-1), to the Wnt signalling molecule, which can prevent the formation of new neurons.

The Dickkopf-1 gene

Prof. Dr. Christof Niehrs. © DKFZ

The Dickkopf-1 gene was discovered by Prof. Dr. Christof Niehrs from the Department of Molecular Embryology at the DKFZ in 1998 while he was working on genes that played a role in vertebrate embryogenesis. The scientists used fertilized Xenopus eggs for their research and also studied early Xenopus stages. Niehrs was particularly interested in the Spemann’s organizer (a region named after Hans Spemann) that organizes gastrulation in vertebrates and has the potential to induce the growth of new organs or even an entire embryo.

The transplantation of Dickkopf genes into Xenopus embryos leads to the development of secondary heads (A). Blocking the Dickkopf protein with antibodies leads to malformations (C); control (B). © Niehrs, Universität Heidelberg

Developmental biologist Hans Spemann was awarded the Nobel Prize in Physiology or Medicine in 1935 for his discovery of the organizer effect in embryonic development. Modern evo devo research over the last few years has clarified the underlying molecular mechanisms. During their investigation of the Spemann’s organizer, Niehrs and his team discovered a gene that, when overexpressed, leads to enlarged heads, which is why it was named Dickkopf (from German “dick” meaning “thick” and “Kopf” meaning “head”; abbrevation: DKK).

The transplantation of the gene can even lead to secondary heads. The Dickkopf protein counteracts Wnt signalling. The gene is a member of a multigene family that is responsible for vertebrate organogenesis. In addition to the DKK-1 gene discovered in Xenopus, humans have three more DKK genes. Mice whose Dickkopf-1 gene is permanently silenced do not have heads. The rest of their body develops normally. 

The same performance levels as young animals

Martin-Villalba and her team found considerably more Dickkopf-1 protein in the brains of older mice than in those of young animals. The researchers suspected that this signalling protein was responsible for the fact that very few new neurons were generated in old age and tested their assumption in mice mutants whose DKK-1 gene was permanently silenced. These mutants were developed at the DKFZ by Professor Niehrs (now founding director of the Institute of Molecular Biology in Mainz and still heading up a group of researchers at the DKFZ). The results were surprising: the hippocampus of two-year-old Dickkopf-1 mutants (which for mice is relatively old) contained 80 percent more new neurons than the hippocampus of 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. The researchers were surprised to see that animals in advanced adult age actually achieved the performance levels of young animals.

“Newborn” neurons (green) in the brain of a three-month-old mouse. © A. Martin-Villalba, DKFZ

Martin-Villalba had previously shown that mice lose their spatial orientation when neurogenesis in the hippocampus is blocked. The researchers used standardized tests to study how the mice orient themselves in a maze. Young (3 months old) mice performed much better in orienting themselves than the older ones (18 months old). In contrast, Dickkopf-1-deficient mice showed excellent spatial orientation and learning capacity. Moreover, older Dickkopf-1 mutant mice also outperformed normal animals in tests determining spatial memory.

The researchers' latest results have attracted considerable attention and sparked speculation as to whether such a substance may also improve the cognitive performance of the human brain, including the maintenance of mental agility and the prevention of age-related forgetfulness. However, this is still a pipe dream. Although it is not yet used for the treatment of cognitive decline, the Dickkopf protein is already being marketed and tested for its potential for use in the treatment of multiple myeloma (bone marrow cancer). But special care must be taken when interfering with the Dickkopf gene - it is not just any gene, it fulfils many different roles in many fundamental developmental processes. Martin-Villalba comments: “It is fascinating to speculate that such a substance may slow down age-related cognitive decline. But this is still a dream of the future, as we have only just begun experiments with mice to explore these questions.”

Desirée 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 12 (2), 204-214. 2013.

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