CORDIS
EU research results

CORDIS

English EN

Genetics to understand cellular components of Alzheimer Disease pathogenesis

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.
Leaflet | Map data © OpenStreetMap contributors, Credit: EC-GISCO, © EuroGeographics for the administrative boundaries

Host institution

VIB VZW

Address

Rijvisschestraat 120
9052 Zwijnaarde - Gent

Belgium

Activity type

Research Organisations

EU Contribution

€ 2 374 997,50

Beneficiaries (1)

Sort alphabetically

Sort by EU Contribution

Expand all

VIB VZW

Belgium

EU Contribution

€ 2 374 997,50

Project information

Grant agreement ID: 834682

Status

Ongoing project

  • Start date

    1 November 2019

  • End date

    31 October 2024

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 2 374 997,50

  • EU contribution

    € 2 374 997,50

Hosted by:

VIB VZW

Belgium