PaquetLab – Neurodegeneration and Vascular Dysfunction
The PaquetLab aims to understand the molecular and cellular mechanisms leading to nerve cell death and cognitive decline in patients with neuropsychiatric disorders (e.g. Alzheimer’s disease, Frontotemporal dementia and related disorders) and neurovascular impairments (stroke and vascular cognitive impairment). We apply cutting-edge technologies, such as CRISPR/Cas genome editing, differentiation of induced pluripotent stem cells (iPSCs) into human brain cells, and tissue engineering to build advanced human in vitro model systems recapitulating disease.
Due to the inaccessibility of human brain cells for molecular research, neurodegenerative diseases have mostly been studied in animal and simplified cellular models, which have significantly broadened our knowledge, but have drawbacks limiting successful translational research. We aim to address this gap by developing human model systems based on iPSCs, which have the genetic configuration of patients. iPSCs allow differentiating and studying somatic brain cell types directly affected by disease, such as neurons, astrocytes, microglia, oligodendrocytes, smooth muscle cells and endothelial cells.
We have recently established protocols for the optimized differentiation of major cell types of the human brain, and also developed efficient technologies to introduce and remove patient mutations using CRISPR/Cas genome editing. In a recent study (Paquet et al. Nature 2016) we have already demonstrated the potential and feasibility of our approach, by generating and studying isogenic sets of human cortical neurons with mutations in the Alzheimer-associated genes. These APP- and PSEN1- mutant neurons displayed Alzheimer-related symptoms.
We aim to extend this work by generating all major cell types relevant for neurodegenerative or neurovascular disease in the human brain from iPSCs, and combining them in a human brain tissue model. In this artificial human brain tissue we aim to elicit and study disease phenotypes and investigate underlying mechanisms. In addition, because such models are accessible for genetic manipulation and amenable to drug development, we plan to apply them for translational studies to accelerate the identification of novel therapeutic approaches and targets.
Professor of Neurobiology
Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich
Room 8G 02 144
D-81377 Munich, Germany
Phone: +49 89 4400 46123