The combination of a newly developed bioinformatic model and experimental data provides new insights into the causes of Alzheimer’s disease. American and German scientists, including scientists from the National Genome Research Network (NGFN), have succeeded in developing a detailed model of the metabolic processes in the brain that enables them to identify disease-causing factors. The researchers found that whilst the activity of a particular enzyme is reduced, specific nerve cells are able to counteract this deficiency by rerouting the metabolic fluxes. Scientists from the University of Heidelberg and the German Cancer Research Center (DKFZ) compared the experimental data with the newly developed analysis software, thereby making a considerable contribution to the study that is being coordinated by Bernhard Ø. Palsson at the University of California.
Alzheimer’s disease is the most common cause of dementia in the elderly. Experiments have shown that the metabolic rates in the different brain regions start undergoing changes several years before the onset of dementia. A new method has made it possible to develop a bioinformatic model which can be used to make specific predictions on the metabolic interactions between multiple cell types. The researchers developed three human brain models representing key metabolic signalling pathways and the reactions of different types of nerve cells, which involve as many as 400 genes.”What we find particularly exciting is that the new models identify genes and pathways that may explain observed experimental phenomena, including the differential effects of the disease on cell types and regions of the brain,” explains Dr. Rainer König, head of a group of researchers at the Department of Integrative Bioinformatics and Systems Biology (iBioS) which involves researchers from the University of Heidelberg and the DKFZ. IBioS is led by Prof. Dr. Roland Eils who was also involved in the current study. “The analyses carried out by myself and my colleague Dr. Gunnar Schramm have shown that some Alzheimer’s patients had a strongly reduced energy metabolism in some brain regions although the cells did not reveal any histological particularities,” explained Dr. König, head of one of the NGFN subprojects. The new bioinformatic models confirm that not all nerve cell types are equally affected by the devastating consequences of Alzheimer’s disease. The models also suggest that the strongly reduced activity of a key enzyme (α ketoglutarate dehydrogenase) plays an important role. It is known that the activity of this enzyme is greatly reduced in Alzheimer’s patients. Some nerve cell types, i.e. the GABAergic neurons, are able to counterbalance the enzyme’s loss of activity by rerouting the metabolic fluxes. Further findings suggest that the enzyme glutamate dehydrogenase (GAD) is responsible for the rerouting. The experimental data support the idea that the enzyme has a protective function, as lower quantities of GAD than normal were found in damaged brain regions of deceased Alzheimer’s patients.The continuous improvement of experimental methods and the generation of new data will contribute to further improving the accuracy of the new models and increasing the accuracy of the predictions. The better the different cell types and brain regions are represented in the model, the greater the benefit the models will bring with regard to gaining a better understanding of the metabolic processes in the brain in general and Alzheimer’s disease, for which currently no cure is available, in particular.