Neuronal Vulnerability In Alzheimer’s Disease
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Posted on Mar 12, 2024, 4 p.m.
Image Credit: National Institute on Aging, National Institutes of Health
The accumulation of protein in discrete populations of brain cells and the degeneration of these cells characterize the early stages of neurodegenerative disorders. However, this selective vulnerability pattern is unexplained for most diseases, yet could hold insight into pathological mechanisms.
Alzheimer’s disease (AD) is defined by the onset of amyloid plaques (extracellular aggregates of Aβ peptides) and neurofibrillary tau tangles (intracellular aggregates of hyperphosphorylated tau, or NFTs). The plaques become widespread in the neocortex and hippocampus, while the NFTs tend to follow a defined regional pattern that starts in principal neurons from the entorhinal cortex.
Researchers from Boston University Chobanian & Avedisian School of Medicine in collaboration with computational genomic experts from Rice University and Karolinska Institute, report in a paper published in the journal Brain, identifying a gene that they believe may lead to the degeneration of the neurons that are the most vulnerable to this debilitating brain-wasting disease.
"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, Ph.D., assistant professor of anatomy & neurobiology at the school.
Using cutting-edge technology and analysis tools with machine learning the team identified the gene DEK as possibly being responsible for the vulnerability of entorhinal cortex neurons to AD. The team injected viruses into the entorhinal cortex of experimental models and neurons grown in the lab to manipulate levels of the gene to reveal that when the levels of the DEK gene were reduced the vulnerable neurons started to accumulate tau and degenerate.
Based on their findings the team suggests that preventing these neurons from degenerating by targeting DEK or proteins that collaborate with the gene could prevent patients from developing memory loss and could curtail disease before it spreads to larger areas of the brain. The team believes that this is the first step in understanding how these fragile neurons die and hopes to discover any additional unknown genes that may be involved to fully understand what leads to the death of these critical memory-forming genes.
"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 co-corresponding author, Patricia Rodriguez-Rodriguez, Ph.D., from Karolinska Institute.
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Image Credit: National Institute on Aging, National Institutes of Health
