Elucidating the Molecular and Cellular Mechanisms Underlying Neurodegeneration Using Advanced Stem Cell-Based Technologies

Project Information

STEMAD3D

Grant agreement ID: 949894

DOI

10.3030/949894

EC signature date 17 December 2020

Start date 1 June 2021

End date 31 May 2028

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 666 957,00

EU contribution

€ 1 666 957,00

Coordinated by

THE HEBREW UNIVERSITY OF JERUSALEM
Israel

Periodic Reporting for period 3 - STEMAD3D (Elucidating the Molecular and Cellular Mechanisms Underlying Neurodegeneration Using Advanced Stem Cell-Based Technologies)

Reporting period: 2024-06-01 to 2025-11-30

Summary of the context and overall objectives of the project

As people around the world are living longer, the number of age-related neurodegenerative diseases is rapidly increasing. Alzheimer's Disease (AD) is the most common neurodegenerative disease with a massive health and financial burden on society. Although our understanding of the mechanisms underlying AD pathogenesis has dramatically improved in recent decades, several unanswered questions remain regarding the disease mechanisms despite substantial research efforts and investment. The underlying disease mechanisms are poorly understood, partly due to the lack of advanced human-relevant models that mimic brain cellular complexity. The overall mission of this ERC grant is to provide an understanding of the cellular and molecular aberrations that underlie AD pathology and neurodegeneration. This project aims to use human-relevant cellular models together with a novel mouse-human xenotransplantation platform to achieve the following objectives:

Aim 1. Defining the molecular and cellular mechanisms that govern neurodegeneration in AD.
Aim 2. Mapping the epigenetic landscape associated with AD.
Aim 3. Dissecting neuroinflammatory interactions underlying AD pathogenesis.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

One of the main questions in this project is to explore the role and the relative contribution of brain's immune and neural systems to disease development. While Alzheimer’s disease (AD) was initially believed to be a neuron-centric neurodegenerative disease, accumulating genetic and functional evidence, along with the chronic neuroinflammation phenotype, indicates that the brain’s resident immune cells, called microglia, play an active role in AD pathogenesis. To investigate these cellular interactions, we focused first on developing the model system, where we established and characterized a human-specific immunocompetent brain organoids system derived from induced pluripotent stem cells (iPSCs). This collaborative study, published in Cell (Schafer*, Mansour*, et al. 2023), provides a novel model system to investigate neuroinflammatory mechanisms underlying AD and elucidate disease-associated microglia/neuronal phenotypes contributing to the disease. We are currently utilizing this platform together with CRISPR/Cas9-edited iPSCs cell lines to assess the molecular and cellular mechanisms that govern the contribution of microglia to AD.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Developing a versatile immunocompetent organoid model is important to the scientific community. This novel model provides an unprecedented opportunity to study the interaction of human microglia with their neuronal environment in healthy and diseased states. By creating a humanized model of AD (as well as other neurological disorders), we hope to gain a better understanding of how the dysregulation of microglia function can lead to neurodegeneration.

Microglia containing Brain Organoid

Microglia containing Brain Organoid