How CSI techniques helped find the trigger for Alzheimer's Disease

Although it's been 15 years since scientists found the causes of Alzheimer's Disease, exactly how it happens has largely been a mystery —until now. Using unconventional experiments and tools, researchers from Cambridge University in the UK were able to retrace the story of how a simple protein gone awry can cause so much havoc to the human brain.

 

Scientists from Cambridge’s Department of Chemistry  discolsed in the Proceedings of the National Academy of Sciences (PNAS) how they were able to identify the molecular trigger for Alzheimer’s that starts a chain of events eventually leading to the death of  brain cells. The results are part of a long-term research project led by Professor Christopher Dobson and his team, 15 years after they discovered the relationship between protein misfolding and Alzheimer’s disease.

 

“We’ve now established the pathway that shows how the toxic species that cause cell death, the oligomers, are formed. This is the key pathway to detect, target and intervene – the molecular catalyst that underlies the pathology”,says  Dr Tuomas Knowles, lead author of the current study. 

Disease backgrounder

 

Alzheimer’s disease and other neurodegenerative conditions happen when beta amyloid, a naturally occurring protein in the brain is misfolded, altering its structure. Imagine the body as a factory and it produces proteins in an assembly line. Somewhere along the line, the production for beta amyloid breaks down, causing it to be assembled differently, adopting a different structure. This change of structure also changes the proteins structure. So instead of performing its intended function, it starts to accumulate and form plaques around the brain. 

 

Scientists understand that this protein damages the brain but how the protein causes so much damage in the first place was heretofore unknown. Samuel Cohen and his team were able to determine the critical level for beta amyloid clumps to trigger a chain reaction, causing the number of protein composites to multiply exponentially. 

Back to the crime scene

 

These composites form small, highly diffusible ‘toxic oligomers’ or protein tendrils that move rapidly around the brain, like a runaway car spinning out of control, killing neurons and interacting with other molecules to cause more damage. The destruction of brain cells is what causes the symptoms of Alzheimer’s like dementia, personality changes, and memory loss.

 

“We are essentially using physical and chemical methods to address a biomolecular problem, mapping out the networks of processes and dominant mechanisms to ‘recreate the crime scene’ at the molecular root of Alzheimer’s disease,” explained Knowles.

 

In order to recreate the "crime scene," the researchers had to use kinetic experiments on a theoretical framework with tools and equipment commonly used in other types of experiments for physics and chemistry. This is one of the few times this kind of kinetic experiments have been used to thoroughly study protein malfunction.

Alzheimer's by the numbers

 

As of 2010, dementia and Alzheimer’s disease affected some 35.6 million people worldwide. This number is expected to double every 20 years, with most of those affected coming from China, India, western Pacific and South Asian countries like the Philippines. It is estimated that by 2050, this number would reach to 115 million.

 

To date, there is still no cure for Alzheimer’s disease. The best treatment available for the disease is focused mainly on managing the symptoms and delaying the debilitating effects. But with these results, scientists and drug manufacturers now have a better idea of what to target.  

 

Knowles explains: “With a disease like Alzheimer’s, you have to intervene in a highly specific manner to prevent the formation of the toxic agents. Now we’ve found how the oligomers are created, we know what process we need to turn off.” — TJD, GMA News