Alzheimer's, Dementia & Mental Health
Age-Related Cognitive Decline Stopped in Older Mice
When Scientists Turn Off Dickkopf-1
Older mice actually produced more neurons and reached
performance level of young animals with silencing of this signaling
7, 2013 - Cognitive decline as we age is linked to the decreasing
production of new neurons. Scientists with the German Cancer Research
Center may have discovered a fountain of youth for the brain. that
keeps the neurons coming. They have discovered that significantly more
neurons are generated in the brains of older mice if a signaling
molecule called Dickkopf-1 is turned off.
In tests for spatial orientation and memory, mice
in advanced adult age whose Dickkopf gene had been silenced reached an
equal mental performance as young animals.
The hippocampus – a structure of the brain whose
shape resembles that of a seahorse – is also called the "gateway" to
memory. This is where information is stored and retrieved. Its
performance relies on new neurons being continually formed in the
hippocampus over the entire lifetime.
"However, in old age, production of new neurons
dramatically decreases. This is considered to be among the causes of
declining memory and learning ability", Prof. Dr. Ana Martin-Villalba, a
Martin-Villalba, who heads a research department at
the German Cancer Research Center (DKFZ), and her team are trying to
find the molecular causes for this decrease in new neuron production (neurogenesis).
Neural stem cells in the hippocampus are
responsible for continuous supply of new neurons. Specific molecules in
the immediate environment of these stem cells determine their fate: They
may remain dormant, renew themselves, or differentiate into one of two
types of specialized brain cells, astrocytes or neurons.
Newborn neurons (in green) in the
brain of a 3 month old mouse
Picture source: German Cancer Research Center
One of these factors is the Wnt signaling molecule,
which promotes the formation of young neurons. However, its molecular
counterpart, called Dickkopf-1, can prevent this.
"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
The scientists tested their assumption in mice
whose Dickkopf-1 gene is permanently silenced. Professor Christof Niehrs
had developed these animals at DKFZ. The term "Dickkopf" (from German
"dick" = thick, "Kopf" = head) also goes back to Niehrs, who had found
in 1998 that this signaling molecule regulates head development during
Martin-Villalba's team discovered that stem cells
in the hippocampus of Dickkopf knockout mice renew themselves more often
and generate significantly more young neurons.
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
Blocking Dickkopf improves spatial orientation
Several years ago, Ana Martin-Villalba had shown
that mice lose their spatial orientation when neurogenesis in the
hippocampus is blocked. Now, is it possible that the young neurons in
Dickkopf-deficient mice improve the animals' cognitive performance?
The DKFZ researchers used standardized tests to
study how the mice orient themselves in a maze. While in the control
animals, the younger ones (3 months) performed much better in orienting
themselves than the older ones (18 months), the Dickkopf-1-deficient
mice showed no age-related decline in spatial orientation capabilities.
Older Dickkopf-1 mutant mice also outperformed normal animals in tests
determining spatial memory.
"Our result proves that Dickkopf-1 promotes
age-related decline of specific cognitive abilities," says Ana Martin-Villalba.
"Although we had expected silencing of Dickkopf-1 to improve spatial
orientation and memory of adult mice, we were surprised and impressed
that animals in advanced adult age actually reach the performance levels
of young animals."
These results give rise to the question whether the
function of Dickkopf-1 may be turned off using drugs. Antibodies
blocking the Dickkopf protein are 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. But this is
still a dream of the future, since we have only just started first
experiments in mice to explore this question."
The German Cancer Research Center (Deutsches
Krebsforschungszentrum, DKFZ) with its more than 2,500 employees is the
largest biomedical research institute in Germany.
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