NEW YORK (GenomeWeb) – University of Cambridge researchers have uncovered a gene expression signature that may portend the development of Alzheimer's disease in healthy people.
As they reported in Science Advances this week, the researchers performed a transcriptome-wide microarray analysis of various brain tissues. They related those results to Alzheimer's disease progression in order to develop a disease vulnerability score that reflects the tendency of proteins in each tissue to aggregate — one of the characteristics of Alzheimer's disease is the buildup of amyloid plaques and neurofibrillary tangles in certain regions of the brain.
The researchers found a correlation between the expression of their signature and disease stage, and they further noted that this expression signature is present in healthy brains.
"[W]hat we've tried to do is to predict disease progression starting from healthy brains," senior author Michele Vendruscolo from Cambridge said in a statement. "If we can predict where and when neuronal damage will occur, then we will understand why certain brain tissues are vulnerable, and get a glimpse at the molecular origins of Alzheimer's disease."
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. "Linking the properties of specific protein molecules to the onset and spread of neuronal damage is a crucial step in the quest to find effective drugs to combat this dreadful neurodegenerative condition, and potentially other diseases related to protein misfolding and aggregation."