An iPSC-derived Human Brain Tissue Model for Alzheimer’s Disease
We currently do not understand well why the brains of Alzheimer patients contain aggregates of proteins and how these aggregates relate to the death of millions of nerve cells over time. To better understand the formation of disease symptoms we aim to generate a human brain tissue model from human induced pluripotent stem cells (iPSCs) that recapitulates major hallmarks of Alzheimer disease (AD), and apply this model to investigate the factors required for formation of pathology.
To generate our proposed model, we will turn human iPSCs into nerve cells, astrocytes and other cell types found in the human brain, and grow them together in a 3-dimensional culture that resembles human brain tissue. The cells will generate a brain-like environment and form typical functional structures and contacts, such as synapses, which allows studying many disease-relevant biochemical processes in the laboratory.
After generating these tissue models, we will introduce disease-relevant alterations in genes, e.g. by inserting mutations leading to inherited forms of AD using CRISPR genome editing, and by modifying cellular physiology in a way that's typical for patients with AD. We will then study formation of Alzheimer pathology in a dish, and investigate approaches to modify or remove symptoms, e.g. by altering the composition of cell types or the function of cells and their genes to learn, which factors cause protein aggregation and nerve cell death in an Alzheimer’s disease brain.
If successful, our work will provide the field with a human brain tissue model containing all major brain cell types and displaying major disease symptoms, which allows not only systematic studies on the mechanisms of disease formation but can also be applied to develop and test novel therapeutic approaches.
Klimmt J, Dannert A, Paquet D. Neurodegeneration in a dish: advancing human stem-cell-based models of Alzheimer's disease. Curr Opin Neurobiol. 2020 Apr;61:96-104. doi: 10.1016/j.conb.2020.01.008. Epub 2020 Feb 26. PMID: 32112992.