Researchers identify gene involved in neuronal vulnerability in Alzheimer's disease

In a new study from Boston University Chobanian & Avedisian School of Medicine, researchers have identified a gene they believe may lead to the degeneration of the neurons that are most vulnerable to AD.

"We are trying to understand why certain neurons in the brain are particularly vulnerable during the earliest stages of AD. Why they accumulate and degenerate very early is unknown. We believe elucidating this vulnerability would allow for a new therapeutic avenue for AD," said corresponding author Jean-Pierre Roussarie, PhD, assistant professor of anatomy & neurobiology at the school.

In collaboration with leading computational genomic experts from Rice University, the BU researchers along with co-corresponding author, Patricia Rodriguez-Rodriguez, PhD, from Karolinska Institute, used cutting-edge analysis tools with machine learning to identify the gene DEK as possibly responsible for vulnerability of entorhinal cortex neurons. They injected viruses into the entorhinal cortex of experimental models and neurons grown in the lab to manipulate levels of the DEK gene. When they reduced the levels of the DEK gene, vulnerable neurons started to accumulate tau and to degenerate.

According to the researchers, preventing these neurons from degeneration by targeting DEK or proteins that collaborate with DEK, would prevent patients from developing memories loss and would curtail the disease before it spreads to larger areas of the brain. "Given that entorhinal cortex neurons are necessary for the formation of new memories and since they are so vulnerable and the first to die, this explains why the first symptom of AD is the inability to form new memories," said Roussarie.

The researchers believe these findings are the first step in understanding how these fragile neurons die, yet they hope to uncover additional genes to fully understand what leads to the death of critical memory-forming neurons.

These findings appear online in the journal Brain.

P.R-R. was supported by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 799638. P.R-R and C.T. were supported by Alzheimerfonden and Margaretha af Ugglas Stiftelse. P.R-R., M.F. and J.P.R. were supported by the Fisher Center for Alzheimer's Disease Research. J.P.R. was supported by Cure Alzheimer's Fund. This study was supported by the National Institute on aging of the NIH (awards RF1 AG054564 and RF1 AG047779 to J.P.R.).

Note: Angel Cedazo-Minguez is an employee at Sanofi.