New thesis paving the way to repair brain damage

Our cognitive functions – to percieve, process and convey information – are governed in the communication between brain cells. Each signal is received and passed on via dendritic processes, small spines on the cell surface whose activity is crucial for us to learn and remember. Damage to brain cells, caused by, for example, neurodegenerative disease or long-term drug abuse, is likely to impair our cognitive functions. Thus, the need is great for a treatment to effectively counteract the process. In the search of potential target structures, Frida Stam is in a new PhD thesis at Uppsala University presenting interesting findings on insulin-regulated aminopeptidase, IRAP.

“IRAP is a protein structure that was identified in fat and muscle cells in 1995. A few years later, IRAP was also discovered in the regions of the brain that are involved in cognitive functions. Here, IRAP affects, among many things, glucose uptake in brain cells and the levels of active signaling substances. By inhibiting IRAP activity, researchers have previously succeeded in improving memory in different animal models, and in my work, we have explored this further with a focus on the cells' vitality and cognitive role,” says Frida Stam, PhD student at the Department of Pharmaceutical Biosciences.

Using the synthetically developed IRAP inhibitors HA08 and C9, Frida Stam has tested the possibility to restore specific mechanisms in brain cells that were damaged in order to mimic the effect of oxidative stress and the use of opioids. The studies were mainly conducted on cells from rats' hippocampus and cortex, two regions of the brain that regulate memory and several other cognitive functions.

“To measure the effect of these IRAP inhibitors, we induced damage in the cells' protective outer membrane and in the mitochondria, best described as the cell’s energy factory. With this method, we could see that the IRAP inhibitors have improving effects on cell viability after induced damage, but also that the number of dendritic spines increases in healthy brain cells.”

In conclusion, Frida Stam notes that her results show that inhibiting IRAP activity will likely generate positive effects on damaged brain cells. Thus, making it an interesting target structure for the regulation of cell damage in specific regions of the brain as well as for the development of new treatments against dementia and other diseases of the brain. Still, Frida Stam accentuates the importance of continued research in order to fully understand and utilize IRAP's full potential.

“We know that IRAP is present throughout the body, affecting many biological systems. This makes IRAP extremely complex and sometimes it seems like the more we discover the more questions appear. In parallel, IRAP is relevant from so many medical perspectives, and if researchers manage to tie all loose ends, it will provide so many important possibilities. Conserning cognitive IRAP-research, a major challenge is to develop stable substances to effectively inhibit IRAP. And when a structure capable of functioning as a drug substance is identified, IRAP inhibitors may well form the basis for new treatments to repair both brain damage and impaired cognitive abilities.”

text: Magnus Alsne, photo: Mikael Wallerstedt, Magnus Alsne