Summary: A gene named DEK has been identified as potentially responsible for the degeneration of neurons vulnerable to Alzheimer’s Disease (AD), particularly in the entorhinal cortex, a critical area for memory formation. By manipulating levels of DEK in experimental models and neurons in vitro, researchers observed increased tau accumulation and neuron degeneration, suggesting a new therapeutic target.
The study offers hope for preventing memory loss and curtailing AD progression by protecting these neurons. This collaborative effort, involving Rice University and Karolinska Institute, signifies a crucial step towards understanding and combating the selective vulnerability seen in AD.
Key Facts:
- Researchers identified the DEK gene as potentially responsible for the degeneration of neurons vulnerable to Alzheimer’s Disease, particularly in the entorhinal cortex.
- Manipulating DEK levels in experimental models led to increased tau accumulation and neuron degeneration, suggesting a novel therapeutic target.
- The study, a collaborative effort between Boston University, Rice University, and Karolinska Institute, provides a crucial step towards understanding the selective vulnerability in Alzheimer’s Disease.
Source: Boston University
Early stages of neurodegenerative disorders are characterized by the accumulation of proteins in discrete populations of brain cells and degeneration of these cells. For most diseases, this selective vulnerability pattern is unexplained, yet it could yield major insight into pathological mechanisms.
Alzheimer’s disease (AD), the world-leading cause of dementia, is defined by the appearance of two hallmark pathological lesions, amyloid plaques (extracellular aggregates of Aβ peptides) and neurofibrillary tangles (intracellular aggregates of hyperphosphorylated tau, or NFTs).
While plaques are widespread in the neocortex and hippocampus, NFTs follow a well-defined regional pattern that starts in principal neurons from the entorhinal cortex.
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.
Funding: 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.).
About this genetics and Alzheimer’s disease research news
Author: Gina DiGravio
Source: Boston University
Contact: Gina DiGravio – Boston University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“A cell autonomous regulator of neuronal excitability modulates tau in Alzheimer’s disease vulnerable neurons” by Jean-Pierre Roussarie et al. Brain
Abstract
A cell autonomous regulator of neuronal excitability modulates tau in Alzheimer’s disease vulnerable neurons
Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer’s disease (AD). Gaining insight into the molecular mechanisms underlying this vulnerability will help reveal genes and pathways at play during incipient stages of the disease.
Here, we use a data-driven functional genomics approach to model ECII neurons in silico and identify the proto-oncogene DEK as a regulator of tau pathology. We show that epigenetic changes caused by Dek silencing alter activity-induced transcription, with major effects on neuronal excitability.
This is accompanied by gradual accumulation of tau in the somatodendritic compartment of mouse ECII neurons in vivo, reactivity of surrounding microglia, and microglia-mediated neuron loss.
These features are all characteristic of early AD. The existence of a cell-autonomous mechanism linking AD pathogenic mechanisms in the precise neuron type where the disease starts provides unique evidence that synaptic homeostasis dysregulation is of central importance in the onset of tau pathology in AD.
