New research published in the journal Brain reveals a new approach to Alzheimer's disease (AD) that may eventually make it possible to reverse memory loss, a hallmark of the disease in its late stages.
The team, led by University at Buffalo scientists, found that by focusing on gene changes caused by influences other than DNA sequences, called epigenetics, it was possible to reverse memory decline in an animal model of AD.
The research was conducted on mouse models carrying gene mutations for familial AD, where more than one member of a family has the disease, and on post-mortem brain tissues from AD patients.
AD results from both genetic and environmental risk factors, such as aging, which combine to result in epigenetic changes, leading to gene expression changes, but little is known about how that occurs.
The epigenetic changes in AD happen primarily in the later stages, when patients are unable to retain recently learned information and exhibit the most dramatic cognitive decline. A key reason for the cognitive decline is the loss of glutamate receptors, which are critical to learning and short-term memory.
The researchers found that the loss of glutamate receptors is the result of an epigenetic process known as repressive histone modification, which is elevated in AD. They saw this both in the animal models they studied and in post-mortem tissue of AD patients.
Understanding that process has revealed potential drug targets, she said, since repressive histone modification is controlled or catalyzed by enzymes.
The AD animals were injected three times with compounds designed to inhibit the enzyme that controls repressive histone modification. The improvements lasted for one week; future studies will focus on developing compounds that penetrate the brain more effectively and are thus longer-lasting.
Brain disorders, such as AD, are often polygenetic diseases, Yan explained, where many genes are involved and each gene has a modest impact. An epigenetic approach is advantageous, she said, because epigenetic processes control not just one gene but many genes.