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Alzheimer's card shows where epigenetics is turning incorrectly



Alzheimer's disease (AD) stems from molecular events, which the researchers bring together to distinguish an overall story, some of which are known, others smaller. Some of the lesser known epigenetic events in Alzheimer's history have just been completed by researchers from the Van Andel Research Institute (VARI). Moreover, these epigenetic events, which occur early in Alzheimer's, seem to fit well with what we know about the progression of the disease to its most devastating biological properties.

The new research center for genetic "volume calls" is called amplifiers, which swing the activity of genes up or down based on influences such as aging and environmental factors. By taking a comprehensive look at enhancers in human brain cells at various stages of Alzheimer's and comparing them with healthy human cells, the VARI researchers found that in Alzheimer's, the acceleration of epigenetic markets has accelerated. Consequently, there is a loss of gene repression so that the affected brain cells are older than they are, making them vulnerable to disease. By overactivating a variety of genes involved in Alzheimer's pathology, the dysregulated enhancers track the formation of plaques and tangles and re-activate the cell cycle in fully-formed cells.

"In adults, brain cells typically perform division. When amplifiers reactivate cell division, it is incredibly harmful," said Viviane Labrie, PhD, VARI assistant professor. "Changes in change we found also stimulate the development of plaques that act as gasoline for the spread of toxic tangles and propagate them through the brain as a firefighter. On the contrary, enhancer abnormalities that promote plaques, tangles and cell cycle reactivation appear to pave the way for brain cell death in Alzheimer's. disease. "

Labrie is a senior author of a paper (" Epigenetic dysregulation of neuronal amplifiers associated with Alzheimer's disease pathology and cognitive symptoms ") that appeared on May 21

in Nature Communications . The paper describes how the VARI team identified 1224 differentially methylated amplification regions; most of which are hypomethylated at CpH sites in Alzheimer's disease neurons.

"Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons," the authors of the articles wrote. "In addition, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene targeted at BACE1. Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles and cognitive decline. "

The new findings unite long-standing theories behind the origin of the disease into a coherent narrative explaining how healthy cells become ill and provide researchers with new opportunities for screening compounds designed to slow or stop disease progression. not do.

Based on their findings and other researchers' suggestions, the VARI team proposes the following model:

  • Hypomethylation of enhancers in DSCAML1 activates BACE1 to induce the formation and progression of both Aβ plaques and neurofibrillary tangle pathology in AD.
  • Interaction of DSCAML1 enhancers with their target BACE1 promoter leads to overproduction of Aβ peptides, which will eventually form plaques. Aβ peptides, in turn, involve the hypomethylation of enhancers which affect ne urogenesis and cell cycle genes that are already primed for activation due to the normative loss of CpH methylation labels with aging.
  • Reactivation of cell cycle genes facilitates tau hyperphosphorylation and, together with Aβ plaques, leads to the formation and spread of tangle pathology resulting in neuronal death and AD cognitive symptoms.

"We now have a better understanding of the molecular factors that lead to Alzheimer's disease, which we can use to develop improved and desperately needed treatment and prevention strategies," Labrie claimed. "Alzheimer's is a major growing public health issue around the world. We need better opportunities for patients and we need them soon."


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