05:49am Wednesday 18 October 2017

Scientists discover a link between the protective effects of cooling on the brain and prevention of neurodegeneration

Research by scientists at the Medical Research Council’s Toxicology Unit, based at the University of Leicester, has identified a protective mechanism that kicks in when body temperature is lowered, activating a process that prevents the loss of brain cells and the connections between them.

The MRC team discovered that this protective process may be defective in neurodegenerative diseases such as Alzheimer’s, contributing to the death of brain cells in these disorders. By simulating the effects of cooling in mice, the scientists have revealed a possible new target for drugs that could protect against neurodegeneration.

It has long been known that during hibernation, where a mammal’s core temperature cools to well below normal body temperature, synapses (the connections between brain cells) are depleted.  This allows the animal to enter a state of ‘torpor’, a state similar to a very deep sleep but where no brain activity occurs, allowing the animal to survive without nutrition for weeks or months.  As the animal comes out of hibernation and warms up, connections between brain cells are reformed and the number of synapses once again rises, restoring normal brain activity.

In humans, a reduction in body temperature (hypothermia) is known to protect the brain.  For example, people have survived hours after a cardiac arrest with no brain damage after falling into icy water.  Artificially cooling the brains of babies that have suffered a loss of oxygen at birth is also used to protect against brain damage.

Cooling and hibernation lead to the production of a number of different proteins in the brain known as ‘cold-shock’ proteins. One of these, RBM3, has been associated with preventing brain cell death, but it has been unclear how it affects synapse degeneration and regeneration.  Knowing how these proteins activate synapse regeneration might help scientists find a way of preventing synapse loss, without the need for actual cooling.

In this study, researchers reduced the body temperature of healthy mice to 16-18ºC – similar to the temperature of a hibernating small mammal – for 45 minutes. They found that the synapses in the brains of these mice, which do not naturally hibernate, also dismantled on cooling and regenerated on re-warming.

The team then repeated the cooling in mice bred to reproduce features of neurodegenerative diseases (Alzheimer’s and prion disease) and found that the capacity for synapse regeneration disappeared as the disease progressed, accompanied by a disappearance of RBM3 levels.

When the scientists artificially boosted levels of RBM3 they found that this alone was sufficient to protect the Alzheimer and prion mice, preventing synapse and brain cell depletion, reducing memory loss and extending lifespan.

The researchers were therefore able to conclude that RBM3 – and perhaps other cold-shock proteins – affects the ability of neurons to regenerate synapses in neurodegenerative diseases, which is essential to prevent synapse loss during disease progression.  The pathway could be a useful target for drugs so that brain cells could be preserved without the need for cooling.

Professor Giovanna Mallucci, who led the research team, said: “We’ve known for some time that cooling can slow down or even prevent damage to brain cells, but reducing body temperature is rarely feasible in practice: it’s unpleasant and involves risks such as pneumonia and blood clots. But, by identifying how cooling activates a process that prevents the loss of brain cells, we can now work towards finding a means to develop drugs that might mimic the protective effects of cold on the brain.”

Professor Hugh Perry, chairman of the MRC’s Neurosciences and Mental Health Board, which funded the research, said: “The neuroprotective pathway identified in this study could be an important step forward. We now need to find something to reproduce the effect of brain cooling.  Just as anti-inflammatory drugs are preferable to cold baths in bringing down a high temperature, we need to find drugs which can induce the effects of hibernation and hypothermia.”

Ends

Notes to editors:

‘RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration’ by Diego Peretti, Amandine Bastide, Helois Radford, Nicholas Verity, Colin Molloy, Maria Guerra Martin, Julie A. Moreno, Joern Steinert, Tim Smith, David Dinsdale, Anne E. Willisand Giovanna R. Mallucci is published in Nature.

For a copy of the paper or to speak to Professor Mallucci, please contact the Medical Research Council press office on email: press.office@headoffice.mrc.ac.uk

The Medical Research Council has been at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Thirty MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. www.mrc.ac.uk


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