Bart De Strooper
VIB-KU Leuven Center for Brain & Disease Research, Department of Neurosciences
GENETICS TO UNDERSTAND CELLULAR COMPONENTS OF ALZHEIMER DISEASE PATHOGENESIS
“We’re very excited to start this project, which will provide us with humanized models for Alzheimer’s disease. We will be able to explore human genetics in human cells in a living brain. We hope to find out how a person’s genetic makeup affects the microglia and astroglia in the context of Alzheimer’s disease. Despite the recent setbacks in clinical trials, we are making fast progress in understanding the disease and using humanized models will bring our findings faster to the patients.”
About the project
Alzheimer disease (AD) is a major health problem worldwide. New therapies require an accelerated translation of genetic information into mechanistic insights. Given limitations of rodent models, fully humanized models are needed to capture the complexity of the disease process. Human stem cells (iPSCs) provide great possibilities but are largely investigated in vitro with associated limitations. Many of the novel genetic risk factors for AD are expressed in microglia and astroglia, which remains an understudied population in this classically neuron-centric field.
We propose here mouse-human chimeric mouse models to test the effects of AD-associated genetic risk factors on the phenotypes of transplanted microglia and astroglia derived from patients and from genomic engineered, isogenic stem cells. The cells will be followed during disease progression in brain of wild type and of mice developing Aβ- and Tau-pathology. Using single cell transcriptomics, a dynamic view of the cell states over time is generated.
In a first arm of the project, we investigate how the genetic makeup of patient derived stem cells with high and low polygenic risk scores influences pathological cell states. In the second arm of the project, we generate inducible CRISPR/CAS9 iPS isogenic cell lines to manipulate rapidly and specifically the expression of four selected AD-associated genes linked to a putative cholesterol pathway but also affecting inflammation. These cell lines will be used also in the second phase of the project when validating hypotheses generated from the extensive bioinformatics analysis of the 600.000 single human cell profiles generated. We expect to identify and validate >5 novel drug targets in the astroglia-microglia axis of AD pathogenesis.
Our work provides humanized models for AD, an answer on how genetic makeup affects microglia and astroglia in an AD relevant context, and establishes a highly versatile platform to explore human genetics in human cells in vivo.