Scientists Pinpoint Gene Linked to Neuronal Susceptibility in Alzheimer’s Disease

Protein buildup and cell degeneration in specific populations of brain cells are hallmarks of the early stages of neurodegenerative diseases.

This selective vulnerability pattern remains unexplained for the majority of diseases, but it may provide important new information about pathogenic mechanisms. The two hallmark pathological lesions that characterize Alzheimer's disease (AD), the most common cause of dementia worldwide, are extracellular aggregates of Aβ peptides called amyloid plaques and intracellular aggregates of hyperphosphorylated tau called neurofibrillary tangles, or NFTs.

Plaques are found throughout the neocortex and hippocampus, whereas NFTs originate from principal neurons in the entorhinal cortex and follow a distinct regional pattern.

Researchers have discovered a gene in a recent study that they think may cause the neurons most susceptible to AD to degenerate.

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.”

Jean-Pierre Roussarie, Ph.D., Corresponding Author and Assistant Professor, Department of anatomy & neurobiology, Boston University Chobanian & Avedisian School of Medicine

Together with co-corresponding author Patricia Rodriguez-Rodriguez, Ph.D., from the Karolinska Institute, the BU researchers collaborated with top computational genomic experts from Rice University to identify the gene DEK as potentially causing entorhinal cortex neuron vulnerability using state-of-the-art machine learning analysis tools.

To change the levels of the DEK gene, they injected viruses into the entorhinal cortex of lab-grown neurons and experimental models. Vulnerable neurons began to accumulate tau and degenerate when they lowered the DEK gene levels.

The researchers hypothesize that by inhibiting DEK or proteins that work in tandem with DEK, they can stop the degeneration of these neurons, preventing memory loss in patients and stopping the disease before it spreads to more extensive brain regions.

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.”

Jean-Pierre Roussarie, Corresponding Author and Assistant Professor, Department of Anatomy and Neurobiology, Boston University Chobanian & Avedisian School of Medicine

Though they hope to find more genes to fully understand what causes the death of essential memory-forming neurons, the researchers feel that these findings are a good starting point for understanding the death of these delicate neurons.

Source:
Journal reference:

Rodriguez-Rodriguez, P., et al. (2024) A cell autonomous regulator of neuronal excitability modulates tau in Alzheimer’s disease vulnerable neurons. Brain. doi.org/10.1093/brain/awae051

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