A novel genetic approach that repairs broken connections between brain cells could lead to treatments that restore memory capacity in Alzheimer's disease.

The new approach reverses changes to gene expression that tend to occur in the later stages of the disease. Scientists at State University of New York at Buffalo demonstrated how the method was able to reverse Alzheimer's memory decline in mice.

Much genetic research on the causes of Alzheimer's disease focuses on changes in the DNA of genes. The new study, however, focuses on epigenetics, which concerns mechanisms that can switch genes on and off without disturbing their DNA code. A paper about the work now features in the journal Brain.

"In this paper," says senior study author Zhen Yan, PhD, who is a professor in the Department of Physiology and Biophysics, "we have not only identified the epigenetic factors that contribute to the memory loss, we also found ways to temporarily reverse them in an animal model of [Alzheimer's disease]."

Alzheimer's disease and loss of synapses

Alzheimer's disease is the leading cause of dementia. According to the World Health Organization (WHO), between 60% and 70% of the 50 million people worldwide who are living with dementia have Alzheimer's.

Most people who develop Alzheimer's disease begin to experience symptoms between the ages of 60 and 70 years. They will have difficulty remembering, thinking, and carrying out simple daily tasks. Eventually, they will not be able to live independently. Although experts do not fully understand the causes of Alzheimer's disease, they suggest that it develops due to a combination of genes, environment, and lifestyle.

One of the distinguishing features of Alzheimer's disease is a type of brain damage that leads to the loss of synapses, which are the junctions between neurons, or brain cells. Signals from one cell pass to another by means of chemical messengers called neurotransmitters, which cross a gap in the synapse.

Epigenetics and glutamate receptors

For communication across synapses to work effectively, brain cells need an abundance of specialized proteins called receptors. One of these, the glutamate receptor, is crucial for short-term memory and learning, says Yan. It appears that the most significant decline in memory and thinking skills occurs in the later stages of Alzheimer's disease, and a major reason for this seems to be the loss of glutamate receptors.

"We found that in Alzheimer's disease," explains Yan, "many subunits of glutamate receptors in the frontal cortex are downregulated, disrupting the excitatory signals, which impairs working memory." She adds that the epigenetic changes that occur in Alzheimer's tend to occur in the later stages of the disease. This is when people struggle to retain new information and experience "the most dramatic cognitive decline."

Various epigenetic mechanisms can switch genes on and off, or upregulate or downregulate their expression. For example, some mechanisms can put chemical tags on a gene's DNA or alter the structure of its packaging to make parts of its DNA more or less accessible to cell processes. Where the gene codes for a protein, upregulation or downregulation will lead to cells making more or less of the protein.

The researchers discovered that the type of epigenetic mechanism that was causing a reduction in glutamate receptors was a packaging-altering one that goes by the name of "repressive histone modification." They found evidence of increased repressive histone modification in the mouse model of Alzheimer's and in postmortem tissues of people with the disease. The epigenetic mechanism downregulates the gene and reduces the production of glutamate receptors. This "leads to loss of synaptic function and memory deficits," says Yan.

New directions for brain disease treatments

As there are enzymes that control repressive histone modification, the findings suggest that drugs that target them could be promising candidates for treating Alzheimer's. In further work with the mouse models, the team confirmed that this was likely to be the case.

Injecting the animals with compounds that block the enzymes led to improvements in working, spatial, and recognition memory that lasted for about 1 week. The improvements also coincided with a "recovery of glutamate receptor expression and function in the frontal cortex," remarks Yan.

Alzheimer's and other such brain diseases rarely link to just one gene. They are usually polygenetic, that is, they involve many genes, each having only a small effect. Yan says that because epigenetic processes often influence several genes, they could offer more fruitful treatment targets for polygenetic conditions.

"An epigenetic approach can correct a network of genes, which will collectively restore cells to their normal state and restore the complex brain function."

—Zhen Yan, PhD