Weak control of inflammation by genes, linked to Alzheimer’s development

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. He and his colleagues conducted a transcriptome-wide microarray analysis of more than 500 healthy brain tissues from the Allen Brain Atlas and characterized the progression of disease using Braak staging. After developing their vulnerability score, the researchers noted that brain regions where Alzheimer’s disease is typically first noticed had elevated expression levels of proteins that co-aggregate in plaques and tangles.

But as these co-aggregating proteins were still present at fairly high levels across the brain, the researchers also examined the role of the protein homeostasis components that regulate them. These components, they found, are typically expressed at lower levels in vulnerable tissues, suggesting a role for them in amyloid and tau deposition.

“Vulnerability to Alzheimer’s disease isn’t dictated by abnormal levels of the aggregation-prone proteins that form the characteristic deposits in disease, but rather by the weaker control of these proteins in the specific brain tissues that first succumb to the disease,” Vendruscolo added.

The vulnerable tissues also exhibited lower expression of genes associated with autoimmune response, which lends further credence to theories that inflammation plays a role in Alzheimer’s disease development.

The researchers repeated their tissue vulnerability analysis for aggregation sets linked to amyotrophic lateral sclerosis, ALS, finding a significant difference between the scores for each disease.

Vendruscolo and his colleagues then used single-cell human mRNA data to zoom in on cells most vulnerable to aggregation by evaluating the levels of amyloid beta and tau in various brain cell types. Their relative expression was highest in neurons, the researchers reported.

“The results of this particular study provide a clear link between the key factors that we have identified as underlying the aggregation phenomenon and the order in which the effects of Alzheimer’s disease are known to spread through the different regions of the brain,” co-author Christopher Dobson, also at Cambridge, said in the statement. ”

Connie’s notes: Reading, using the brain more, exercise, sleep, whole foods and being out in the sun (Vit D helps in absorption of calcium and magnesium) help in slowing the progression of Alzheimer’s (as we age, we move less, our body function slowly, so we need to energize our body more).