Researchers have used a mouse model to show that heart problems can lead to disruptions in gene activity in the memory center of the brain, a region called the hippocampus; from that, cognitive problems arise. The findings, which can help explain why the risk of dementia goes up in individuals with heart problems, have been reported in EMBO Molecular Medicine. In this work, the cognitive problems could be alleviated in the mouse model with a drug that affects gene expression. It could aid in the design of new therapeutics for dementia.
As we age, the heart can become weak, and it may become enlarged as it struggles to pump blood through the body. This heart disease can severely affect health and quality of life. It also raises the risk of dementia.
"People with cardiological problems and heart failure in particular may experience noticeable cognitive deficits and increased risk of developing Alzheimer's disease. Possible reasons include impaired blood supply to the brain and dysfunction of the hippocampus, which is the memory's control center," explained André Fischer, research group leader at the German Center for Neurodegenerative Diseases (DZNE) and professor at the Department of Psychiatry and Psychotherapy at the University Medical Center Göttingen (UMG).
"Yet, there is a lack of therapies to effectively treat cognitive deficits in people with heart problems. This is because it is completely unclear which deficiencies are triggered in neurons. There was no data on this so far."
In this study the scientists confirmed that the mice model of heart problems also had problems with cognition, then they investigated gene expression in the hippocampus, a known center of learning.
"In memory tests, mice with heart failure performed significantly worse than their healthy mates," Fischer explained. "We then examined the neurons of the hippocampus. In the mice with heart failure, we found increased cellular stress pathways and altered gene activity in neurons."
The work showed that there were changes in how the DNA was compacted in the neurons of mice with heart problems compared to healthy mice. These kinds of structural changes can affect which parts of the genome are available, and which genes can be expressed, in a cell. In this work, the scientists found that in the heart diseased mice, the DNA was wound more tightly around the histone proteins that organize the genome in the nucleus of a cell - in this case, mouse hippocampal neurons, than normal mice.
"Genes can only be active if they are accessible to the cell's machinery. To this end, the DNA needs to be wound a little more loosely at the relevant sites. This is similar to a ball of yarn with loops sticking out of it," said Fischer.
The structure of the genome is one of several, changeable aspects of the genome that can affect gene expression - epigenetics. Previous work by this team has shown that a drug approved for cancer treatment, vorinostat, can treat age-related memory problems that have a genetic cause, in mice. The DZNE is now conducting a human trial to see if vorinostat can help Alzheimer's patients. This work showed that while the drug doesn't fix the heart problems in their mouse model, it did alleviate their memory issues.
"Vorinostat has been shown to act on histones and thus on gene activity. Our study thereby provides initial clues about the molecular processes that contribute to cognitive dysfunction following heart problems, and it indicates potential approaches for therapy. Fact is, however, that we do not yet understand why, as a result of heart failure, gene activity in the hippocampus is disturbed" noted Fischer.
"What is the role of the deficient blood supply to the brain? Does the troubled heart release substances that affect the histones? We intend to investigate this in patients with heart problems. As with our current study, which involved experts from neuroscience and cardiac research, we aim to address these questions in an interdisciplinary way."