Summary: Researchers have identified a specific gene signature in brain regions that are most vulnerable to Alzheimer’s disease.

Source: University of Cambridge

Gene Signature in Healthy Brains Predicts Regions Vulnerable to Alzheimer’s Disease

Researchers at the University of Cambridge have identified a gene expression signature in healthy brains that mirrors the pattern in which Alzheimer’s disease later progresses across the brain. Published in Science Advances, the study reveals molecular features that may explain why some brain regions are more susceptible to Alzheimer’s than others. These findings offer a potential path toward preventative strategies and better-targeted research models for this debilitating neurodegenerative disease.

The research team analysed more than 500 samples of healthy human brain tissue from public atlases to search for patterns that could predict the tissue-specific progression of Alzheimer’s disease. They discovered that a group of genes related to protein homeostasis—cellular systems that control protein folding and prevent harmful aggregation—shows a distinctive expression pattern in the brain areas that typically develop Alzheimer’s pathology first.

Alzheimer’s disease is marked by progressive degeneration of brain tissue and the accumulation of two misfolded proteins: amyloid-beta (Aβ) and tau. These proteins form the characteristic extracellular plaques and intracellular neurofibrillary tangles associated with the disease. Although age-related loss of cellular defence mechanisms contributes to aggregate formation, this study indicates that the baseline strength of those defences differs between brain regions even in young, healthy individuals.

The investigators found that the vulnerable regions do not necessarily have higher levels of aggregation-prone proteins. Instead, those regions show weaker expression of the protein homeostasis components that normally regulate and clear misfolded forms of Aβ and tau. In other words, tissue-specific differences in the molecular systems that manage protein quality control appear to underlie the characteristic pattern of disease spread from the entorhinal cortex into neocortical areas.

“We aimed to predict disease progression from healthy brains,” said Professor Michele Vendruscolo, senior author of the study and a member of the Centre for Misfolding Diseases in the Department of Chemistry at Cambridge. “Understanding where and when neuronal damage is likely to occur gives us insight into the molecular origins of Alzheimer’s disease and points to new strategies for prevention.”

Because the gene signature is detectable in healthy brains long before symptoms typically appear, it could help identify individuals who are at elevated risk of developing Alzheimer’s and who might benefit most from early preventative interventions. The study supports the idea of enhancing natural protein homeostasis mechanisms as a therapeutic direction—strengthening the cellular defences that keep Aβ and tau soluble and functional could slow or prevent aggregation.

Earlier work from this research group proposed the concept of “neurostatins”—compounds that would bolster protein homeostasis in the brain in a way analogous to how statins are used to lower cardiovascular risk. The current findings suggest a reliable molecular marker that could be used to select those individuals most likely to gain from such early preventive treatments when and if they become available for human use.

Beyond informing preventative strategies, the gene signature can improve the design of animal and cellular models of Alzheimer’s disease. Because existing models rarely reproduce the full complexity and regional progression of human pathology, understanding the molecular environment that predisposes particular brain regions to aggregation may enable the creation of more faithful experimental systems. Better models will accelerate drug discovery and the testing of interventions that target the earliest stages of disease development.

Lead author Rosie Freer, a PhD student in the Department of Chemistry, noted that the molecular features identified may also have relevance for other age-related neurodegenerative diseases characterized by protein aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and frontotemporal dementia. Recognizing common mechanisms of tissue vulnerability could broaden the impact of these findings across multiple disorders linked to impaired protein homeostasis.

Co-author Professor Christopher Dobson added that linking the properties of specific protein molecules and their regulatory systems to the spatial and temporal pattern of neuronal damage is a crucial step toward effective therapies. “This study provides a clear connection between the factors that underlie protein aggregation and the order in which Alzheimer’s disease progresses through different brain regions,” he said.

About the study

This study—“A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease”—reports a transcriptional analysis that correlates histopathological staging of Alzheimer’s disease with expression patterns of proteins that coaggregate in plaques and tangles, together with components of the protein homeostasis network that regulate Aβ and tau. The expression signature identified in healthy brains offers an explanatory link between a tissue-specific environment for protein aggregation and subsequent vulnerability to Alzheimer’s disease.

Source: Sarah Collins, University of Cambridge. Original research published in Science Advances on August 10, 2016.

Suggested citation formats

MLA: University of Cambridge. “Gene Signature in Healthy Brain Pinpoints Origins of Alzheimer’s Disease.” NeuroscienceNews, 10 August 2016.

APA: University of Cambridge. (2016, August 10). Gene Signature in Healthy Brain Pinpoints Origins of Alzheimer’s Disease. NeuroscienceNews.

Chicago: University of Cambridge. “Gene Signature in Healthy Brain Pinpoints Origins of Alzheimer’s Disease.” NeuroscienceNews. Accessed August 10, 2016.

Keywords: Alzheimer’s disease, gene signature, protein homeostasis, amyloid-beta, tau, brain vulnerability, preventative treatment, neurostatins, University of Cambridge, Science Advances.