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

Informazioni relative al progetto

STEMAD3D

ID dell’accordo di sovvenzione: 949894

DOI

10.3030/949894

Data della firma CE 17 Dicembre 2020

Data di avvio 1 Giugno 2021

Data di completamento 31 Maggio 2028

Finanziato da

• EXCELLENT SCIENCE - European Research Council (ERC)

Costo totale

€ 1 666 957,00

Contributo UE

€ 1 666 957,00

Coordinato da

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)

Periodo di rendicontazione: 2024-06-01 al 2025-11-30

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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