The research, conducted by scientists at the University of Adelaide and the National Institutes of Health, in the United States, explains why clinical trials of drugs targeting proteins in the brain that were thought to cause dementia and Alzheimer’s have failed.
“For decades, scientists have thought that dementia and Alzheimer’s Disease are caused by protein aggregates forming in the brain. But recent clinical trials of drugs that reduce the aggregates have failed,” said project leader Professor Robert Richards, from the University of Adelaide’s School of Biological Sciences.
Professor Richards said inflammation had long been known to correlate with neurodegeneration and until recently this relationship was seen as one of consequence rather than cause – with inflammatory cells and events acting to “clean up the mess” after neurological injury.
The researchers assembled evidence from a wide range of human studies and animal models of dementia-related diseases and found that inflammation is at the very least, rate-limiting for neurodegeneration and more likely, a principal underlying cause in most if not all neurodegenerative diseases.
The finding opens the way for potential new treatments with existing anti-inflammatory drugs.
“We know that inflammation has different phases – early on it can be protective against a threat by actively degrading it, but if the threat is not removed, then persistent inflammation actually causes cell death,” said Prof Richards.
The new work turns previous thinking around. The genetic linkages imply that the inflammation comes first, and the tissue damage second.
“Many genes linked with dementia operate at the level of controlling cellular inflammation. Both internal and external triggers interact with these genes to play a part. Inflammation is the point through which many triggers converge,” said Prof Richards.
“Inflammation is a very effective defence against foreign agents like viruses. But as we get older and accumulate mutations, our cells can make proteins and DNA products that mimic viruses, and these build up in the system.
“Normally, our cells bar-code their own products to tell them apart from foreign agents. When these barcodes aren’t in place, our cells can’t properly distinguish ‘self’ and ‘non-self’ trigger molecules. The result is inflammation that escalates and spreads – hence the term auto inflammatory disease.”
Certain types of gene mutation cause these systems to fail earlier or more often, and can increase with age – possibly accounting for age-related increased risk of developing dementia. By reducing some elements of inflammation, it may be possible to reduce dementia symptoms.
“With this new understanding of the disease, we now need to test existing anti-inflammatory drugs for their effectiveness in treating dementia,” Prof Richards said.
The study is published online in the journal Human Molecular Genetics.Jump to next article