Less than a decade ago, when Dr. Hansruedi Mathys embarked on an ambitious quest to create an annotated library of gene readouts from 100 individual brain cells, the endeavour seemed overwhelming. However, with rapid technological advancements, Mathys has now successfully mapped the ‘transcriptomes’ of 1.3 million brain cortex cells from 48 individuals, both with and without Alzheimer’s disease.
Mathys, a pioneer in single-cell transcriptomic analysis on post-mortem human brain tissue during his postdoctoral training, is now an assistant professor of neurobiology at the University of Pittsburgh School of Medicine. He believes that the resulting atlas of the ageing human brain offers crucial molecular insights into the brain’s vulnerability and resilience.
“I am extremely interested in understanding the phenomenon of cognitive resilience where, despite the characteristic signs of Alzheimer’s tissue pathology, individuals display no cognitive impairment,” Dr. Mathys stated. “Our recent findings have made me more hopeful than ever that it might be possible to artificially induce such resilience in people who otherwise are susceptible to memory loss.”
The study, published this week in Nature, involved collaboration with researchers at the Massachusetts Institute of Technology. They analysed the transcriptomes of cells across six distinct brain regions commonly affected by Alzheimer’s pathology. The resulting atlas, now available online to researchers worldwide, serves as a valuable tool for gene and molecular discovery across pathways affecting brain health.
By tracking how transcriptomic changes are linked to cognitive decline and Alzheimer’s pathology, Mathys and his colleagues identified that astrocytes—cells that form the brain tissue scaffold and perform other crucial functions—might hold a key to cognitive resilience.
Mathys’ ongoing research, stemming from the transcriptome mapping, aims to explore the functional significance of altering astrocyte metabolic pathways to impact cognitive function. “There is still a lot to learn about Alzheimer’s disease and the human brain,” said Mathys. “This project is just the beginning.”
