Is there a link between head injury and dementia?

Research project: Do inflammatory mechanisms cause Alzheimer's disease following brain injury?

Lead Investigator: Dr Jill Fowler
Institution: University of Edinburgh
Grant type: Fellowship
Duration: 4 years
Amount: £179,000
Start Date: May 2010
End date: August 2015

What was the project, and what did the researchers do?

People who have previously experienced severe head or whiplash injuries in the past are thought to be at greater risk of developing dementia. Research suggests that this may be caused by an immune reaction (inflammation) that occurs following head injury.  Such inflammation can lead to formation of the toxic clumps of the amyloid and tau proteins that are hallmarks of Alzheimer's disease. 

Dr Fowler has previously developed a mouse model of brain injury. She showed that injury leads to increased levels of proteins associated with Alzheimer's disease, such as amyloid. The same trend was seen in brain tissue of people with dementia.

In this project the researchers carried out three separate but related projects, all in mice. 

  • Firstly they identified which proteins were altered in response to mild traumatic brain injury. 
  • Secondly they looked to see if, in brain injury caused by reduced blood supply, antioxidant and anti-inflammatory proteins that might protect the brain from damage are switched on. They also used a drug (dimethyl fumarate (DMF) that switches these proteins on, to see it reduces disease
  • Thirdly, they asked whether too much of a particular protein (the NMDA receptor) that plays a role in the formation of memory increases the chances of brain damage occurring.

What were the key results and how will this benefit people with dementia?

Experiment 1: Proteins involved in mild traumatic brain injury

Three proteins were strongly switched on following mild brain injury. One (glial acid fibrillary protein (GFAP)) had been noted before, and two (chloride intracellular Channel 4 (CLIC4) and SV2b) were novel and merit further research.

Experiment 2: Ability of a novel drug to reduce brain damage after injury

Several anti-inflammatory genes were indeed switched on after brain injury, and this was boosted by the drug DMF. There was improvement in brain cell function, and they began studies on how this happened. 

Experiment 3: Studying cell death following brain injury

In the third experiment, they identified a small part of one of the proteins which forms the NMDA receptor (GluN2B) is responsible for mediating cell death.  This could aid drug design.

What happened next? Future work and additional grants

Dr Fowler has been awarded a senior research fellowship from Alzheimer's Research UK. 

How were people told about the results? Conferences and publications

Papers

McQueen J. et al. (2014) Restoration of oligodendrocyte pools in a mouse model of chronic cerebral hypoperfusion.  PLoS One 9(2): e87227. 
Martel MA et al. (2012) The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults.  Neuron. 2012 74(3):543-56. 
Bell KFS et al. (2011) Activation of Nrf2-regulated glutathione pathway genes by ischemic preconditioning.  Oxidative Medicine and Cellular Longevity.1155/2011/689524. Epub 2011 Jun 28.
Horsburgh K et al. (2011) Axon-glial disruption- the link between vascular disease and Alzheimer's disease? Biochemical  Society Transactions, 39(4):881-5.
 

Bell KFS et al. (2011) Mild oxidative stress activates Nrf2 in astrocytes which contributes to neuroprotective ischemic preconditioning. Proceedings of the National Academy of Sciences  108(1)E1-2
 

Spain A et al. (2010) Mild fluid percussion injury in mice produces evolving selective axonal pathology and cognitive deficits relevant to human brain injury.  J Neurotrauma 27(8):1429-38

Conferences 

The work was presented at 13 conferences in the UK, France and the USA.

Other dissemination activities

Oral presentations to lay audiences
Two presentations on 'The links between head injury and Alzheimer's Disease' at the annual Alzheimer's Society conference, and at an Alzheimer's Research UK funded public lecture in 2010.

Written presentations to lay audiences

Fellowship update (2013) Alzheimer's Society Research newsletter, June/July, issue 127, p11.

Categories

Further reading