Project Overview

Challenge: Alzheimer’s disease (AD) is characterized by a decline in cognitive function, yet it is now widely acknowledged that as the disease advances, dopaminergic neurons in the midbrain become particularly vulnerable, leading to non-cognitive symptoms such as motor dysfunction. While microglia, the immune cells resident in the central nervous system, have been implicated in neurodegenerative diseases, including AD, their role in the specific loss of dopaminergic neurons remains poorly understood.

Solution: This research project focuses on elucidating the role of microglia in conditions conducive to the progressive loss of dopamine neurons in AD induced pluripotent stem cells (iPSC)-derived 3D model. Characterization involves the assessment of microglia activation, their phagocytic capacity, phenotypic and transcriptomic changes, global proteomic changes, and their impact on dopamine neurons within 3D neuronal models. Spatial transcriptomics will also be applied to analyze the transcriptomic landscape of microglia in these immunized midbrain organoids (iMOs) to identify AD-associated gene expression changes. Building on these readouts, CRISPR technology will be used to target specific genes towards evaluating their effects on microglial function and dopamine neuron survival under various insults. This screening platform enables the identification of key genes and pathways involved in microglial-mediated midbrain degeneration.

Expected Achievements/Impact: This research project deepens our understanding into the involvement of microglia in midbrain degeneration and address the critical knowledge gap regarding the role of microglia in dopamine neuron loss. The knowledge gained from this research has the potential to identify novel therapeutic targets and strategies for the treatment of diseases involving dopamine neuron loss, such as AD and other neurodegenerative disorders.

Principal Investigator

Thomas Durcan , Montreal Neurological Institute and Hospital, McGill University

Partners and Donors

CQDM

Merck Canada