Sunday, 20 May 2012

Forgetful Mice Leading the Way in Alzheimer’s Research - Ellie van der List


Alzheimer’s disease is a neurodegenerative disease which causes severe dementia and ultimately death. It is predicted that by 2050, one in eighty people world-wide will be affected by the disease. At present, due to the complete reliance on carers, Alzheimer’s disease is one of the most costly diseases in developed countries. Alzheimer’s disease is caused by a build-up extracellular plaque produced by malfunctioning neurons. This plaque causes structural and functional damage to the surrounding neurons which results in decreased cognition and memory formation.


So far there isn’t a cure. However, exciting new research using histone deacetylasing inhibitors could change that.
A study by Kilgore et al. in 2010 used a line of mice with mutations in two of the genes known in humans to be responsible for the early onset of Alzheimer’s disease as a mouse model of Alzheimer’s disease.  The study was testing the effects of histone deacetylasing inhibitors. Histone deacetylasing proteins are responsible for the compacting of DNA tightly around the histone proteins. DNA that is tightly condensed is inaccessible to transcriptional machinery and is effectively turned ‘off’. By inhibiting these proteins, histone deacetylasing inhibitors do not allow for this process and are inadvertently allowing DNA to be turned ‘on’ more easily.
Kilgore et al. hypothesise that because the acetylation of the DNA in the neurons in the hippocampus is necessary to form long term memory, deacetylasing inhibitors will enhance the abilities of Alzheimer’s afflicted mice to form contextual memory.
They tested the mice’s memory abilities by introducing the mice into a chamber, allowing them to explore and orientate themselves with in the chamber, and then stunning them with a mild electric shock. Then they were reintroduced to the chamber 24 hours later and the experimenters analysed the mice’s behaviour to assess whether they could associate the chamber with a previous sense of fear.  Without any treatment, the normal mice could remember that the chamber was a place to fear, whereas the Alzheimer’s mice couldn’t remember.
After treatment however, the histone deaceytlases inhibitors caused the Alzeimer’s mice to react the same way as the wild type mice. In other words, the mice that were genetically engineered to have Alzhimer’s disease and present with the symptoms of dementia, were about the form the same memories as the normal mice. The researchers had restored the normal phenotype!
LTM: Long Term Memory Test
The histone deacetylasing inhibitor (SAHA) is associated with a significant increase in freezing behaviour (the behavioural response to remembering the electric shock chamber) in the Alzheimer’ mice (APP/PS1) compared to the control (Veh).
 

 















This is a very exciting finding for those involved in searching for a cure for Alzheimer’s disease. However there is much work yet to be done until histone deacetylase inhibiting drugs hit the market. It just not yet known how, or which specific types of histone deacetylasing inhibitors reduce the neurological impairment associated with Alzheimer’s disease. The research by Kilgore et al. has provided serious support for further studies which are currently performing human trials to see whether histone deacetylasing inhibitors could be successful in treating Alzheimer’s disease in humans.

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