Heart problems cause disruption of gene activity in the brain’s memory center

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Heart problems cause a disruption in the activity of genes in the brain’s memory center, causing cognitive deficits. Researchers from the German Center for Neurodegenerative Diseases (DZNE), University Medical Center Göttingen (UMG) and the German Cardiovascular Research Center (DZHK) come to this conclusion based on laboratory studies.

They believe they have found a possible cause for the increased risk of dementia in people with heart problems. In mice, a specific drug known to affect gene activity alleviated mental deficits. The experts involved see these results as potential approaches for therapy. Data from the study are published in the scientific journal “EMBO Molecular Medicine“.

In Germany, around four million people are affected by what is called “heart failure”: their heart muscle is too weak to pump enough blood through the body and is therefore abnormally enlarged. Physical condition and quality of life suffer. In addition, those affected have an increased risk of developing dementia.

“People with cardiological problems and heart failure in particular may have noticeable cognitive deficits and an increased risk of developing Alzheimer’s disease. Possible reasons include insufficient blood supply to the brain and impaired functioning of the brain. ‘hippocampus, which is the control center of memory “, explains André Fischer, head of the research group at the DZNE site in Göttingen and professor in the department of psychiatry and psychotherapy at the UMG.

“Yet there is a lack of therapies to effectively treat cognitive deficits in people with heart problems. This is because there is absolutely no clear what impairments are triggered in neurons. There were none. data on this so far. “

Stressed cells

From now on, a team led by Prof. André Fischer and Prof. Karl Toischer (Cardiology and Pulmonology Clinic of the UMG and the DZHK site in Göttingen) is presenting results on this subject for the first time. Researchers observed in mice that altered gene activity developed in the hippocampus as a result of heart problems.

In memory tests, mice with heart failure performed significantly worse than their healthy companions. We then looked at the neurons in the hippocampus. In mice with heart failure, we found increased cellular stress pathways and altered gene activity in neurons. “

André Fischer, research group leader, German Center for Neurodegenerative Diseases, Göttingen site

Tight windings

The genome of a mouse – and also of humans – consists of around 20,000 genes. In any given cell, however, only a portion of them are active, lit, so to speak. It is not a simple on or off state: the activity can be strong or weaker. It depends, among other things, on how DNA (the threadlike molecule that carries the genome) is coiled and the accessibility of the genes it contains. In mice as in humans, DNA is over a meter long.

But in a cell, the molecule is so tight that it fits into the nucleus. “Genes can only be active if they are accessible to the machinery of the cell. For this, the DNA must be coiled a little more loosely at the sites concerned. This is similar to a ball of yarn with loops sticking out. of it, “says Fischer. In the current study, DNA was found to be more tightly coiled in the neurons of mice with heart problems than in healthy partners. Various genes important for hippocampal function were therefore less active than in healthy mice.

A drug that improves memory

Scientists have identified chemical changes in histones as the cause of the tight coiling. Histones are special proteins: DNA wraps around them, much like thread around a spool of thread. Fischer’s research group has been studying histones and other players that influence gene activity for some time – in technical jargon, they’re called “epigenetic mechanisms.”

In this context, researchers are also studying drugs. In previous studies, they were able to show that the anti-cancer drug “vorinostat” can relieve genetically and age-related memory problems in mice. Currently, vorinostat is being studied for the treatment of people with Alzheimer’s disease in a clinical trial of DZNE.

In the current study, scientists treated mice with heart failure with this drug. They found that the heart’s pumping capacity did not change significantly, but memory performance improved.

Interdisciplinary cooperation

“It has been shown that vorinostat acts on histones and therefore on gene activity. Our study thus provides initial clues to molecular processes that contribute to cognitive dysfunction following heart problems, and indicates potential therapeutic approaches, ”commented Fischer of the findings.

The point is, however, that we do not yet understand why, as a result of heart failure, gene activity in the hippocampus is disrupted. What is the role of insufficient blood supply to the brain? disturbed heart release substances that affect We intend to study this in patients with heart problems.As with our current study, which involved experts in neuroscience and cardiac research, we aim to address these issues in an interdisciplinary manner. “

Source:

Journal reference:

Islam, R., et al. (2021) Epigenetic gene expression links heart failure to impaired memory. EMBO Molecular Medicine. doi.org/10.15252/emmm.201911900.

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