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'Hibernation protein' could help repair dementia damage

Thursday 15 January 2015

"Neurodegenerative diseases have been halted by harnessing the regenerative power of hibernation," BBC News reports. Researchers have identified a protein used by animals coming out of hibernation that can help rebuild damaged brain connections – in mice.

Research found the cooling that occurs in hibernation reduces the number of nerve connections in the brain, but these regrow when an animal warms up.

A protein called RNA-binding motif protein 3 (RBM3) increases during the cooling, and it appears this protein is part of a pathway involved in the regrowth.

When the level of RBM3 was increased without cooling, researchers found the protein protected against the loss of nerve connections in mice with early-stage rodent forms of Alzheimer’s disease and a prion infection similar to Cruetzfeldt-Jakob disease (CJD). The diseases progressed more quickly when the level of RBM3 was lowered.

This same protein is increased in humans when they are given therapeutic hypothermia, where the body temperature is reduced to 34C as a protective treatment after events such as a heart attack.

The hope is that restoring neural connections (synapses) in humans could halt, or even reverse, the effects of dementia and associated neurodegenerative diseases. But this research is still very much in the early stages.

Where did the story come from?

The study was carried out by researchers from the University of Leicester and the University of Cambridge, and was funded by the Medical Research Council.

It was published in the peer-reviewed journal, Nature.

On the whole, the media reported the study accurately, but the Mail Online got carried away when they said a drug produced from this research "given in middle age … could keep the brain healthy for longer".

The experiments have only been done in mice so far, and no drug has been developed to target the pathway in humans.

What kind of research was this?

This was an animal study that looked at the effects of hibernation on the brain synapses (nerve connections) of mice.

Normally, synapses in the brain go through a process of forming, being removed, and then forming again. Various toxic processes can cause more degeneration, and in some conditions they are not reformed.

This leads to a reduction in the number of synapses, as occurs in conditions such as Alzheimer's disease, which are associated with symptoms such as memory loss and confusion.

A similar loss of synapses occurs when animals hibernate, but they are renewed when the animal warms up at the end of hibernation. Previous research found this also happens when rodents are cooled in a laboratory setting.

Researchers found the production of many proteins does not occur at these low temperatures, but some proteins called "cold-shock proteins" are stimulated – one of these is RBM3.

Here, the researchers wanted to further investigate whether this protein plays a role in the regeneration of synapses. They hope it might be key to understanding how we could restart the process of synapse renewal in humans.

What did the research involve?

Three groups of mice were studied during hibernation induced in the laboratory setting:

  • normal (wild type) mice – controls
  • mice with a rodent form of Alzheimer's disease
  • mice with a prion disease, similar to Cruetzfeldt-Jakob Disease (CJD)

Some mice were cooled to 16-18C for 45 minutes and then gradually warmed back to their normal body temperature.

Their brains were studied at various stages of the cooling and rewarming process to count the number of synapses and measure the level of RBM3.

Some mice with the prion disease were not cooled so they could be used as a comparison to see if the cooling process had any effect on the course of the disease.

The other mice were also not cooled, but their levels of RBM3 were chemically increased or decreased to see what effect this had on their brains.

What were the basic results?

Normal mice and mice with the very early stages of a rodent form of Alzheimer's disease (at two months) and a prion disease (at four and five weeks after infection) lost synapses as they were cooled down, but recovered them as they warmed up.

They also all had increased levels of RBM3 during the cooling stage. These levels of RBM3 stayed elevated for up to three days afterwards.

The prion-infected mice did not succumb to the disease as quickly as mice that had been infected but not cooled.

They survived for seven days longer on average (91 days compared with 84 days). This suggests the cooling process gave some protection against the prion disease.

Mice who had rodent Alzheimer's disease for three months and a prion disease for six weeks (that is, more advanced disease) also lost synapses when they were cooled, but were not able to regrow them on warming up.

They did not have increased levels of RBM3. There was no difference in survival between these prion-infected mice and the prion-infected mice that were not cooled.

In mice where RBM3 levels were artificially reduced, both types of disease worsened more quickly and synapses were lost faster.

Reducing RBM3 levels in mice without these diseases also reduced the number of synapses, and the mice had memory problems.

When RBM3 production was stimulated in one region of the brain (the hippocampus) in mice with prion infection, this reduced the number of synapses that were lost and increased their survival.

How did the researchers interpret the results?

The researchers concluded the protein RBM3 is involved in the pathway of synapse regeneration in mice. They found stimulating the protein was protective against synapse loss in mice with a rodent form of Alzheimer's disease and a prion disease. They hope that, with further research, this might be a new avenue for drug development for humans.


The researchers have shown how cooling is protective against the loss of synapses in the early stages of rodent forms of Alzheimer's disease and a form of prion disease. Cooling also increased how long prion-infected mice survived.

But cooling was not protective in the later stages of the diseases. The researchers found this may in part be because of the protein RBM3, which is stimulated during cooling. They found levels of RBM3 increased in the early stages of the diseases when the mice were cooled, but did not in the later stages.

Stimulating this protein without cooling the mice also slowed down the loss of synapses and improved survival in mice with a prion infection.

The results also showed the disease processes sped up when RBM3 levels were reduced. The researchers say this indicates RBM3 is likely to be involved in the maintenance of synapse connections under normal conditions, not just during hibernation.

It is already known from other studies that similar increases in RBM3 occur when humans are given therapeutic hypothermia, where the body temperature is reduced to 34C as a protective treatment – for instance, after a heart attack.

It may be the case that if this pathway is stimulated in humans, it could be a new avenue of research for the treatment of neurodegenerative disorders such as Alzheimer's disease.

This is intriguing research, but still very much in its early stages. There is much we don't know about Alzheimer's disease and other related diseases, though there is evidence that taking steps to maintain a healthy blood flow to the brain by taking regular exercise and eating a healthy diet may lower the risk (as well as help prevent heart disease).

Read more about dementia prevention.

Analysis by Bazian
Edited by NHS Website