Frida Stam: Inhibition of Insulin-regulated aminopeptidase in the brain: Evaluation of cognitive markers and restorative effects

Abstract

Cognitive functions like learning and memory, are natural abilities that humans are highly dependent on to function properly. Neurological disorders like dementia, ischemia, and substance-use disorder may all severely impair cognitive functions. The complexity of the brain and its neurobiology make it challenging to develop potent new therapies that can prevent the onset of disease or relieve symptoms. Few new drugs have been successful in the last decades, thus new targets are wanted. In 1995, a new aminopeptidase member was discovered in fat and muscle cells, the insulin-regulated aminopeptidase (IRAP). IRAP is expressed in many different tissues, including several regions of the brain associated with cognition. The endogenous hexapeptide angiotensin IV (AngIV) and similar ligands binds to IRAP, and causes inhibition of its enzymatic activity. This inhibitory intervention is suggested to improve cognitive functions.

The overall aim of the present thesis was to investigate the effects of inhibiting IRAP in the brain. The project has focused on studying restorative effects, cognitive markers, and effects on memory performance using the synthetic IRAP inhibitors HA08 and compound 9 (C9). These two IRAP inhibitors improved cellular function in damaged primary neuronal cultures, an effect that was more prominent in hippocampal cell cultures. The difference in effect between hippocampus and cortical cell cultures may be linked to the composition of cell types and the expression pattern of IRAP in these regions. C9 was also demonstrated to have positive effects on drebrin expression, a protein highly concentrated in dendritic spines. Furthermore, C9 regulated the distribution of microtubule-associated protein 2 (MAP2) positive neurons and glial fibrillary acidic protein (GFAP) positive astrocytes, key markers for improved synaptic activity and cognitive functions, in primary neuronal cultures. Although many positive results were obtained from the in vitro studies, behavioural studies on male rats did, however, not demonstrate any effects on memory performance after an acute HA08 administration. 

In conclusion, the findings in the present thesis confirm that IRAP-inhibition can induce positive effects on cellular health, and increase the expression of proteins important for synaptic plasticity. These results further indicate that IRAP may be involved in cognitive mechanisms, and strengthens IRAP as a potential target for treatment of different neurological diseases.