The brain's adaptation to hibernation has given scientists a promising lead on a potential treatment for Alzheimer's disease.

Photo Credit: Matthias Klaiber | CC BY-NC-SA 2.0

For humans, hypothermia can be fatal – but many animals endure extreme cold for months on end during the winter season. Now, scientists studying how the brain temporarily shuts down in the cold have revealed that neurons disconnect from one another in response to low temperatures, and rely on a particular protein to reconnect when the cold abates. The team also shows this protein has a protective effect – a finding with therapeutic implications for brain diseases like Alzheimer's.


Previous studies have shown that a unique class of proteins called cold-shock proteins help protect the brain from damage during periods of hypothermia. While the body's protein-production usually slows down in the cold, production of cold-shock proteins actually ramps up. Intrigued by these findings, scientists from the University of Leicester decided to investigate the effects of one protein in particular, RNA-binding motif 3 (RBM3), to better understand how it and other cold-shock proteins manage to protect the brain.

Reporting their results in Nature, the research team, led by Diego Peretti, subjected mice to brief, artificial hibernation in a laboratory setting. The team employed mouse models of two neurodegenerative diseases in the hopes of understanding how hypothermia might influence the onset of brain damage. Neuroscientist Graham Knott explains more in Nature News and Views:

In their study, Peretti and colleagues subjected mice modeling Alzheimer's disease and mice infected with prions (proteins that cause neurodegenerative diseases such as Creutzfeldt–Jakob disease) to deep hypothermia, with the animals' body temperatures being reduced from 37 °C to 16–18 °C for 45 minutes. The authors identified and counted the synaptic connections between neurons using electron microscopy, and found that, during hypothermia, the number of contacts dropped significantly in a region of the brain implicated in memory formation — the hippocampus. After young animals had been warmed up, the number of synapses returned to normal.

In older animals, the same loss of synapses occurred, but the recovery did not. The effects on RBM3 also differed in old and young animals: whereas levels of RBM3 rose in response to the temperature drop in young mice, they failed to do so in older ones. Although the researchers found no symptoms of neurodegeneration in older animals on the basis of histological sections, biochemical measurements or behaviour, these mice were presumably further along the road to disease.

The same way someone might shut the water mains to an unoccupied cabin in August, to prevent pipes from freezing and bursting in the winter, the synaptic connections between neurons in the hippocampus are temporarily disabled for the duration of the cold.

Additionally, the production of RBM3 seemed to correlate with the reemergence of these synapses upon warming. However, this was only observed in young animals, who had yet to progress towards inevitable disease. An outline of a remarkable sequence of events was ermerging: Hypothermia led to increased RBM3 which in turn had a protective effect on the brain. But the researchers needed further proof.


To shore up their findings, the scientists cold-shocked young, prion-infected animals twice in the course of one week. The treatment not only bumped up RBM3 levels for two months (an eternity for a mouse), but staved off the terminal stages of prion disease. In one case, this treatment extended the lifespan of a prion-infected animal by 50%.

Older animals, unable to produce more RBM3 in response to the cold, were not aided by the dual hypothermia treatments. Furthermore, when the scientists genetically interfered with RBM3 production, this protection-by-hypothermia was lost, suggesting that RBM3 itself might be responsible.


To test the role of RBM3, the researchers artificially increased the protein's production in a group of prion-infected mice, and achieved the same protective effects as the hypothermia treatments. The mice experienced an extended lifespan, and delayed behavioral symptoms of brain disease. This one protein could stave off the progressive deterioration of synapses and brain tissue in a mouse model of neurodegeneration.

While RBM3 is nowhere ready for clinical trials in humans, this discovery opens many doors for further work towards effective treatments for diseases like Alzheimer's. What is RBM3 doing to preserve the ability of neurons to assemble and disassemble their connections in response to the cold? Could cold itself be used to ward off Alzheimer's in people with a family history of the disease?

A true cure for Alzheimer's has yet to be discovered, but there is clearly still much hope, and much to be learned about the resilience of our brains.


Read the full scientific study in Nature.

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