Project description
Mouse-human brain chimeric models in Alzheimer's research
Discovery of effective therapies for Alzheimer’s disease requires application of humanised models for better understanding of genetic information associated with the disease. Human stem cells provide new possibilities to investigate Alzheimer-associated genetic risk factors affecting brain microglia and astroglia. This EU-funded project aims to develop unique chimeric mouse-human models to analyse genetic risk factor effects on phenotypes of transplanted microglia and astroglia derived from patients and from engineered stem cells. Research will obtain information about particular genetic risk factors and how they correlate with the phenotypes of the cells derived from patients. In conclusion, project work will create very valuable humanised mouse models as a versatile platform for the investigation of human genetics in vivo.
Objective
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 (iPS) 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 Crisper/CAS9 iPS isogenic cell lines to manipulate rapidly and specifically the expression of 4 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.
Fields of science
Keywords
Programme(s)
Topic(s)
Funding Scheme
ERC-ADG - Advanced GrantHost institution
9052 ZWIJNAARDE - GENT
Belgium