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Alzheimer's disease (AD) stems from molecular events that scientists are reconstructing to give a global story, some of which are well known, others less so. Some of the lesser known epigenetic events in the history of Alzheimer's have just been completed by scientists based at the Van Andel Research Institute (VARI). Moreover, these epigenetic events, which occur early in Alzheimer's disease, seem to correspond well to what we know of the progression of the disease towards its most devastating biological characteristics.
The new discoveries focus on genetic "volume dials" called activators, which activate or inhibit the activity of genes based on influences such as aging and environmental factors. By exhaustively examining the activators in the brain cells of people at different stages of Alzheimer's disease and comparing them to the cells of healthy people, VARI scientists have found that the loss of epigenetic marks is accelerated in Alzheimer's. . As a result, there is a loss of gene repression, so the affected brain cells act older than they are, making them vulnerable to the disease.
By excessively activating a series of genes involved in Alzheimer's pathology, dysregulated amplifiers stimulate plaque and entanglement formation and reactivate the cell cycle in fully formed cells.
"In adults, brain cells are usually divided. When stimulants reactivate cell division, it's a lot of damage, "said Viviane Labrie, PhD, assistant professor at VARI. "The enhancement modifications we found also encourage the development of plaques, which act like gasoline for the spread of toxic entanglements, spreading them in the brain like wildfire. Overall, enhancement abnormalities that promote plaque, entanglement, and cell cycle reactivation appear to open the way for cerebral cell death in Alzheimer's disease. "
Labrie is the lead author of an article ("Epigenetic dysregulation of activators in neurons is associated with the pathology of Alzheimer's disease and cognitive symptoms") was published on May 21 Nature Communications. The paper describes how the VARI team identified 1224 differentially methylated activator regions; most of which are hypomethylated at the CpH sites in neurons of Alzheimer's disease.
"The integration of epigenetic and transcriptomic data demonstrates a proapoptotic reactivation of the cell cycle in post-mitotic AD neurons," the authors of the article wrote. "In addition, AD neurons have a large group of significantly hypomethylated amplifiers in the DSCAML1 gene that targets BACE1. The hypomethylation of these activators in AD is associated with upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline. "
The new findings bring together long-standing theories about the origin of the disease into a coherent narrative that explains how healthy cells get sick and gives scientists new ways to screen compounds designed to slow or stop the progression of the disease. disease, what existing drugs can not do.
On the basis of their results and those of other researchers, the VARI team proposes the following model:
- The hypomethylation of amplifiers in DSCAML1 activates BACE1 to induce the formation and progression of Aβ plaques and neurofibrillary tangling pathology in AD.
- The interaction of DSCAML1 activators with their target BACE1 promoter leads to overproduction of Aβ peptides, which will eventually form plaques.
- Aβ peptides, in turn, engage in the hypomethylation of enhancers affecting the neurogenesis and cell cycle genes, which are already ready for activation due to the normative loss of methylation marks of CpH with aging.
- The reactivation of the cell cycle genes facilitates the hyperphosphorylation of tau protein and, with Aβ plaques, leads to the formation and spread of an entanglement pathology, resulting in neuronal death and cognitive symptoms of MA.
"We now have a better understanding of the molecular factors that cause Alzheimer's disease, which we can rely on to develop improved and absolutely necessary treatment and prevention strategies," says Labrie. "Alzheimer's disease is a major and growing public health problem worldwide. We need better options for patients, and we need them soon. "
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