Alzheimer's disease and epigenetics
According to a preclinical study by a group of scientists from the University of Buffalo, memory impairment associated with Alzheimer's disease can be restored by inhibiting enzymes involved in abnormal gene transcription. The findings may provide a key to the discovery of new treatments for Alzheimer's disease.
Alzheimer's disease is accompanied by a change in gene expression in the prefrontal cortex, the area of the brain that controls cognitive processes. By focusing on gene changes caused by epigenetic processes such as aging, the researchers were able to reverse the increased activity of pathological genes that cause memory deficits in Alzheimer's disease.
DNA Packaging
Gene transcription is regulated by an important histone modification process, when histones, proteins that are involved in packing DNA into chromosomes, are modified to make this packing looser or denser. This, in turn, determines how the genetic material gets access to the transcriptional mechanism of the cell, which can lead to the activation or suppression of certain genes.
The researchers found that the modification of histones H3K4me3 (trimethylation of histones in the amino acid lysine 4), which is associated with the activation of gene transcription, is significantly increased in the prefrontal cortex of patients with Alzheimer's disease and mouse models of this disease.
This epigenetic change is caused by an abnormally high level of histone-modifying enzymes that catalyze the modification of H3K4me3. The researchers also found that when mice with Alzheimer's disease received a compound that inhibited these enzymes, their cognitive functions improved significantly.
A new target
Researchers have identified a number of new target genes, including Sgk1, as the main target gene for epigenetic change in Alzheimer's disease. In the prefrontal cortex of the brain of people with Alzheimer's disease and animal models of this disease, the transcription of Sgk1 is significantly increased. According to the authors, abnormal methylation of histone in Sgk1 contributes to its increased expression. Interestingly, Sgk1 activation is also strongly correlated with cell death in other neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis.
The Sgk1 gene encodes an enzyme that is activated by cellular stress. The researchers found that it is closely related to other altered genes in Alzheimer's disease, and can probably function as a kind of center that interacts with many molecular components to control the progression of the disease.
The introduction of a compound inhibiting Sgk1 significantly reduced the level of pathological tau protein, which is one of the signs of Alzheimer's disease, restored the synaptic function of the prefrontal cortex of the brain and reduced memory deficit in animals with Alzheimer's disease. These results confirmed that the Sgk1 gene is a potential target for the development of a new treatment for Alzheimer's disease, which can be specific and targeted.
Article Q.Cao et al. Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer's disease is published in the journal Science Advances.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of University at Buffalo: Study: Memory deficits resulting from epigenetic changes in Alzheimer's disease can be reversed.