Senile Dementia: Wrong spooling

15. September 2010

Irreversible? A working group in Goettingen/Germany showed with mice that weakness of memory in older age is connected with faults in the DNA chromatin framework. And it is possible to reverse that with suitable active agents. Should these results get confirmed when it comes to human beings, we might be able to play a trick on evolution.

If it is true what German and Chinese researchers found out and published just recently, functional decline of traffic connections in the brain starts at the sweet age of three to four years. Starting in our forties, our memory slows down noticeably and at the age of 85, more than half of the people suffer from morbus Alzheimer. What could be the reasons why pathways and synapses are not functioning any more? Crossing from normal concentration- and memory problems to dementia often comes smoothly. The role, characteristic Alzheimer-plaques in the CNS plays, is by far not cleared yet.

Neuro-epigenetics determine memory performance

A paper of researchers at the Goettingen University, made in cooperation with the Max-Delbrueck-Center in Berlin, now shows that decreasing memory performance might be the result of an increasing number of mistakes in the chromatin framework of the DNA. Already several years ago, experiments pointed into the direction that storage of experience and memories in the hippocampus and the frontal cortex might be based on a modification of histones and DNA. Histones here function like “spools” where the DNA string is coiled properly. Modifications with methyl- phosphor- and acetyl groups are seeing to the machinery getting access to the code for reading genes. The hippocampus also is the place in the memory where a decreasing memory performance becomes visible first. If the histones are missing the right acetyl groups, the cell cannot read the according genes any more. Important functions for memory building malfunction – the road to dementia begins.

Shahaf Peleg and Andre Fischer and their team selected mice in the age of three, eight and sixteen months for their tests. Having a life span of a bit over two years, the oldest test animals thus were in their early senior age. It was harder for their memory to learn a correct reaction to certain stimulations. Those deficits reflected in the nerve system: When the researchers examined histone proteins in the hippocampus, they found a specific deregulation of one of the proteins (histone H4) not acetylating an amino-acid rest. But if the central nervous system cannot activate especially those genes connected to learning and memorizing, extensive detours become necessary. Old rodents are dim.

Senility is reversible

But in further experiments, the team found out that this process is reversible. Once they block the enzyme which removes acetyl left-overs (= histone-deactylase), the memory of the mice improved. The according genes of the nerve cells in the hippocampus were active once again. Whether the according inhibitor is capable of reversing memory impairment in old people is not sure though. Other tests show that for example in old monkeys and mice other genes in the brain are active than in human beings. It also is rather unlikely that a single amino-acid left-over of a chromatin-protein is responsible for degeneration of our memory, as David Sweatt at the University in Birmingham/Alabama in the US remarks critically in an accompanying comment in Science. Numerous experiments have proven though that activity of sirtuins, the known histone-deactylases, is tightly connected to the aging process.

Evolution: Does longevity make sense?

Control processes in the aging brain are not only connected to degeneration as shown recently by researchers at the Max Planck Institute for Evolutionary Anthropology in Leipzig in cooperation with colleagues in Shanghai in an article in the professional magazine Genome Research. They examined regulation proteins, DNA transcripts and micro-RNA-molecules in the prefrontal cortex of humans and rhesus macaques in different age groups. Their results prove that the decrease of active genes in nerve cells starts very early, often already in pre-school age. These changing processes in the brain necessary for the development from child to adult thus continue as a normal aging process all the way through to the old person subtly loosing his or her memory. Philipp Khaitovich and the other authors say that after the reproduction phase, a long life is no longer meant to be the most important target of evolution.

EPITHERAPY: With DNA-technology against Alzheimer & Co.

Nonetheless, the results of the chromatin examinations might lead to a higher quality of life down the road. In all probability the number of Alzheimer-patients will double within the next 20 years. Reason enough to participate on clearing this with funding, also for the EU. The working group in Goettingen cooperates with laboratories in Spain and France on the project EPITHERAPY (An epigenetic approach towards the recovery of neuronal network plasticity and cognitive function in neurodegenerative disease). Those typical defects of histone acetylisation during decreasing memory performance might serve as markers for a beginning dementia in the future. It would be perfect if they would even be the target for substances working as spark plugs getting an ‘out of operation’ neuro-engine in the central nervous system running again.

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