A Human Brain-In-A-Dish Model to Investigate Central Factors Required For the Formation of Alzheimer’s Disease Pathology

Dominik Paquet, PhD
Institute for Stroke and Dementia Research, University Hospital, LMU Munich (Munich, Germany)
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2022
Disease:
Alzheimer's Disease
Award Amount:
$0
Grant Reference ID:
A2019604S
Award Type:
Standard
Award Region:
International
dominik paquet

An iPSC-derived Human Brain Tissue Model for Alzheimer’s Disease

Summary

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 these disease symptoms we would like to investigate the building blocks that are required for the formation of Alzheimer pathology. For this purpose, we will turn human stem cells into nerve cells and other cell types found in the human brain, grow them together in a dish to assemble artificial human brain tissue, and introduce alterations in genes and cellular physiology that are typical for patients with inherited forms of Alzheimer’s disease. We will investigate if these models display Alzheimer pathology in a dish, and then modify the composition of cell types or the function of cells and their genes to learn, which factors cause protein aggregation or nerve cell death in an Alzheimer’s disease brain.

Details

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.

About the Researcher

Dr. Dominik Paquet received his PhD in 2009 from the Ludwig-Maximilians-University (LMU) in Munich, Germany, where he successfully developed the first transgenic zebrafish model of Tauopathies and demonstrated its suitability for in vivo drug screening and real-time in vivo imaging of disease processes. During his postdoctoral work with Marc Tessier-Lavigne at The Rockefeller University in New York City, which was supported by the German Academy of Sciences Leopoldina and The New York Stem Cell Foundation, Dr. Paquet entered the novel field of induced pluripotent stem cell (iPSC) based disease modeling. He built up a new iPSC laboratory at Rockefeller and developed efficient technologies to edit the genome of iPSCs by CRISPR/Cas9 editing to study Alzheimer’s and other neurodegenerative diseases in human brain cells. As a New York Stem Cell Foundation Druckenmiller Fellow, he was embedded in a thriving network of top-notch stem cell scientists, which allowed him to gain profound knowledge of related fields of stem cell research and strong ties with the stem cell community. Dr. Paquet established the PaquetLab (www.isd-research.de/PaquetLab) at the Institute for Stroke and Dementia Research (ISD) of LMU Munich in 2017 and currently serves as Professor of Neurobiology and core member of Synergy (www.synergy-munich.de), a leading Research Cluster of the Excellence Initiative of the German research funding organization. Using his broad background in neurodegenerative disease research, with specific training and expertise in molecular, stem cell and neurobiology, he leads an interdisciplinary team of neurobiologists, biochemists and stem cell biologists. The PaquetLab uses cutting-edge technologies such as CRISPR genome editing, iPSC differentiation and human 3D tissue engineering to elucidate the molecular function of the human brain and the mechanisms leading to neurodegenerative and neurovascular diseases.

Personal Story

I was always fascinated by the way nature works and already wanted to become a scientist when I was a child. I studied biology, because I was most interested in fundamental processes, but during my studies I became increasingly interested in diseases. In addition, I was totally fascinated by the function of one of the most complex systems that nature created, the human brain. I therefore decided that I wanted to work in Neuroscience.

When I started my PhD I became 'infected' by the enthusiasm and passion of my PhD advisor Christian Haass for investigating the molecular mechanisms of neurodegenerative diseases. But when going through the literature and discussing with my mentors I also felt the need of the field for novel, enriching research approaches to overcome hurdles in understanding disease mechanism and developing drugs. During my PhD I therefore developed a fully translucent zebrafish model of Alzheimer and related Tauopathies, which for the first time allowed high-throughput drug screening and live imaging of disease progression in a complete animal.

During my postdoctoral work, I changed into the nascent field of disease modelling in induced pluripotent stem cells (iPSCs), which for the first time promised to allow experimental studies in human brain cells. I developed and established several crucial technologies to bring the field closer to an iPSC-based disease model of Alzheimer’s disease, such as genome editing with the newly invented CRISPR/Cas genome editing system. After starting my own research lab in 2017 I decided to build my further career on these highly promising technologies and dedicated my lab to developing human brain tissue models to investigate mechanisms of Alzheimer, other dementias, and also other brain diseases. I strongly believe that the human brain tissue models we develop have the potential to greatly advance the field – not only to better understand human specific disease pathways, but also by allowing to develop and test drugs in a human system and thus increasing transferability to patients. 

Publications

Klimmt J, Dannert A, Paquet D. Neurodegeneration in a dish: advancing human stem-cell-based models of Alzheimer's disease. Curr Opin Neurobiol. 2020 Feb 26;61:96-104. doi: 10.1016/j.conb.2020.01.008. [Epub ahead of print] Review.PubMed PMID: 32112992 PubMed Icon Google Scholar Icon

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