MitoModels

Due to increased life expectancy, the prevalence of neurodegenerative diseases such as Alzheimer's disease (AD) or Parkinson's disease (PD) will continue to rise in the coming years. Currently there is only one symptomatic therapy for PD, whereas in AD even this one suffers from a lack of effectiveness (cholinergic therapy approaches). Consequently, the development of new therapeutic approaches is at the centre of drug development. A major obstacle to drug development is the lack of relevant models for predominant sporadic forms of these diseases. Models used so far are based on the analysis of (1) rare, genetically determined familial forms of disease (e.g. amyloid hypothesis), (2) inflammatory processes or (3) neuroprotective mechanisms. To date, no approach has led to successful target structures based on therapeutic hypotheses. However, studies on cellular systems and animal models suggest that mitochondrial functions play a major role in both AD and PD.

This project is based on the assumption that aging processes such as age-related reduction of the mitochondrial energy balance contribute to the development of various neurodegenerative diseases, which then manifest themselves in various specific disease patterns according to further genetic or environmental influences. Consequently, an animal model with restricted mitochondrial functions will be developed for neurodegenerative diseases. RNA interference methods will be used for the development of transgenic rats in which the expression of mitochondrial key enzymes is reduced. In addition to phenotyping the new model, the influence of known pharmacological inhibitors or RNAi constructs against GSK3beta or CDK5 on the brain will be investigated.

At the NMI, lentiviral shRNA vectors are generated to reduce the expression of mitochondrial genes as well as GSK3beta and CDK5. GSK3beta and CDK5 are known target structures for AD. Suitable constructs against mitochondrial genes are used to generate transgenic rats. These rats in turn are phenotyped at the NMI for histological features (qualitative and quantitative analysis of synapses in brain slices). They will also be used to investigate the contribution of the known AD target structures GSK3beta and CDK5 after RNA interference in the new animal model on a histological level.