Neuronal networks in vitro: from rat to men

Abstract

In 2015 almost 50 million people worldwide suffered from dementia in which the performance of complex brain tasks gradually declines. In advanced stages patients need help with basic activities of daily living, which has an enormous socioeconomic impact. The underlying processes involved in complex tasks of the brain are organized by neuronal networks. Specialized structures called synapses are responsible for communication between neurons and networks. The most common form of dementia is Alzheimer’s disease (AD), which is a neurodegenerative disorder characterized by abnormal protein deposition in the brain and synaptic deficits. Extracellular aggregation of beta amyloid (plaques) and intracellular tangles of tau protein (neurofibrillary tangles) develop in the cortex and hippocampus (an important brain area involved in memory) in particular. The distribution of tau pathology in time and space correlates well with nerve cell degeneration and cognitive decline. Other neurodegenerative disorders called tauopathies show similar tau pathology. The low accessibility of live human neurons for research forces researchers to use and develop representative models. Animal models have been indispensable for the current knowledge about the human brain, but the complexity of the human brain can hardly be mimicked. Despite the prevalence and high socioeconomic impact of these cognitive disorders there is inadequate knowledge about disease onset and mechanisms and no disease-modifying treatments are available. Most experts agree about the involvement of complex interactions between genetic and environmental factors in tauopathies, but clinical trials are afflicted by high attrition rates. Therefore, new research methods and therapeutic strategies have to be tested. The recent generation of pluripotent stem cells from human somatic cells enables the differentiation of patient-derived cells to almost all relevant cell types. This way, human neurons containing the complete genetic background of a patient can be studied in vitro. The aim of this thesis is exploration of the opportunities to use these human neuronal cells as a model for cognitive disorders, with tauopathies as a specific application. The results of this thesis show a robust and reproducible differentiation protocol from stem cells towards human functional neuronal networks in vitro. Using various imaging based approaches networks were characterized further. Starting from this protocol two tauopathy models were proposed and neuronal networks were studied. In addition to the development of tau aggregation, other tauopathy-related phenotypes were identified which might be used for research concerning onset and progression of tau pathology and possible treatment options. The presented data in this thesis show the potential to use the recently developed human stem cells to study processes involved in human brain function. The combination of different approaches seems inevitable, but comparison of this technology with previously described animal models can possibly replace animal studies and bridge the gap with the clinical manifestation of disease.