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Genetic 'reshuffling' by brain cells may link to Alzheimer's disease

26 November 2018
Appeared in BioNews 977

For the first time, genetic 'reshuffling' has been shown to occur in cells in the human brain. This could shed light on the development of Alzheimer's disease and may even explain why current treatments for the disease have been so unsuccessful. 

Mutations in a gene called APP have previously been shown to cause Alzheimer's disease. Researchers studying this gene found evidence of genetic 'reshuffling' – or somatic recombination – occurring in neurons in the brain. In a new study, they found that there were thousands of variants of the APP gene, which supported previous hypotheses that somatic recombination occurs in the brain. 

This work, which was published in Nature, has been called a 'landmark study' by Dr Christos Proukakis, a clinical neurologist from University College London who was not involved in the research.  

In the study, brains of deceased individuals were analysed, including six healthy samples and seven with Alzheimer's disease. Professor Jerold Chun and his colleagues at the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California discovered that although recombination happens in both healthy and diseased brains, there are many more variants of the APP gene in individuals with Alzheimer's disease. 

The protein that the gene codes for is linked to the build up of amyloid plaques in the brain, which define the presence of Alzheimer's disease. Researchers found 11 mutations of APP in neurons of brains with Alzheimer's disease, and none those mutations were present in healthy brains. 

Professor Chun said: 'At the moment, it's unclear why the APP gene is able to morph into different forms. In healthy people, it may give the brain greater flexibility by letting it produce a wider repertoire of signalling proteins.' They also didn't know why the gene appeared to 'shape shift' more frequently in the brains of people with Alzheimer's, Professor Chun said. 

The increased number of APP variants in brains of people with Alzheimer's disease could be producing a range of toxic chemicals. Current attempts to treat Alzheimer's disease by targeting the amyloid plaques might have been unsuccessful because there are thousands of other toxic products, Professor Chun added. 

The researchers suggest that the different variants of the APP gene could depend on an enzyme called reverse transcriptase. If this is the case, then drugs that block this enzyme – reverse transcriptase inhibitors – could be used to treat Alzheimer's disease. Reverse transcriptase inhibitors are already used in HIV treatment, so these drugs are approved for use in humans and could quickly be transferred to treatment of Alzheimer's disease. 

However, other specialists in the field have cautioned against using HIV drugs as treatment prematurely. Scientists 'just don't have the data yet' to support the use of HIV drugs for Alzheimer's, said Professor Steven Wolinsky, a virologist from Northwestern University's Feinberg School of Medicine in Chicago, Illinois, who was not involved in the study.

Professor Chun next plans to investigate the effectiveness of HIV drugs to treat Alzheimer's in mice.  

SOURCES & REFERENCES
'Landmark study' shows brain cells revamp their DNA, perhaps sparking Alzheimer’s disease
Science |  21 November 2018
Morphing brain DNA hints at a whole new way to treat Alzheimer's
New Scientist |  21 November 2018
Somatic APP gene recombination in Alzheimer’s disease and normal neurons
Nature |  21 November 2018
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