Cambridge scientists map vulnerability to Alzheimer’s in healthy brain

Posted on 10th August 2016

Science Advances: A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease.

A team of researchers from the University of Cambridge has studied data from healthy human brain tissue, revealing a signature of proteins in specific areas of the brain that could dictate vulnerability to damage in Alzheimer’s. The findings help to explain the characteristic spread of damage across the brain that is observed in the disease and the findings could help to inform future drug discovery efforts. The results are published on 10 August in the journal Science Advances.

Alzheimer’s disease is characterised by the abnormal build-up of two proteins in the brain called amyloid and tau. Initially, the damage inflicted by both proteins is confined to specific areas of the brain – particularly those involved in controlling memory and navigation. Over time, the damage caused by these proteins spreads across the brain, affecting new areas and causing symptoms to worsen and diversify. This spread of damage is not random and for many years researchers have observed a predictable pattern of spread between particularly vulnerable areas of the brain. But researchers have long questioned why these areas are most susceptible to Alzheimer’s.

The Cambridge team suggested that one explanation for this vulnerability could lie in the pattern of proteins expressed in a particular brain area. If a region of the brain expresses a signature of proteins, which are inherently more prone to clumping together, then it could be more susceptible to the damage triggered when the amyloid and tau proteins start to build up.

To explore their hypothesis they used data from existing databases to compare the levels of almost 20,000 genes and corresponding proteins from 500 different brain areas taken from six healthy people aged 24 to 57 years. They gave a vulnerability score to each brain region that was higher if that area expressed more proteins that were prone to clumping together. They then looked to see whether these protein signatures corresponded to the areas of the brain known to be most susceptible to damage in Alzheimer’s.

The scientists found a link between areas of the brain known to be vulnerable to damage in Alzheimer’s and specific signatures of genes and proteins in those areas. The gene signature corresponded to proteins that either clump together with amyloid and tau, or influence the brain’s ability to clear the two culprit proteins.

Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, said:

“These findings suggest that our susceptibility to Alzheimer’s may not only be dictated by abnormal changes in the brain, but by how our brains are hardwired to react to those changes. For many years scientists have been trying to understand why some parts of the brain appear more vulnerable to Alzheimer’s and these results point towards a biological explanation. This study only focuses on healthy brains, but reveals a signature of proteins in certain areas of the brain that could predict susceptibility to the build-up of hallmark Alzheimer’s proteins later in life.

“Understanding the molecular mechanisms that underpin susceptibility to diseases like Alzheimer’s has the potential to open the door to new treatment and prevention approaches. Building a complete picture of the biology driving a complex disease like Alzheimer’s gives scientists the best chance of developing effective treatments against it.”

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