Deciphering the microglia-neuron interactions in human Alzheimer's disease

The goal of this project is to decipher the exact cellular and molecular mechanisms by which human microglia transduce toxicity to neurons in Alzheimer's disease (AD). Genetics revealed that microglia are one of the central players in the pathogenesis of AD. I and others have characterized the phenotypic response of microglia in AD using transcriptomic and epigenetic tools.

Nevertheless, it is yet to be defined how microglia communicate with other cells in the brain, by which mechanism they lead to neuronal alterations, and what the particular role of different microglial activation states is in this process.

I will investigate the two major functional outputs of microglia - namely physical interaction with synapses and release of inflammatory factors that induce neuronal dysfunction and degeneration - in AD.

Determining the role of human microglia in AD comes with technical challenges, including lack of homology between mouse and humans, and limited expression of AD risk genes in mouse microglia.

I will use a human microglia xenograft model I pioneered where iPSC-derived cells are transplanted into the mouse brain, and in which they adopt a brain resident phenotype and can be exposed to amyloid-b plaques.

I plan to combine xenotransplantation of genetically engineered iPSC-derived microglia and neurons, with state-of-the-art strategies to define the human microglia-synapse protein interactome as well as the cell-specific proteome/secretome.

I aim to 1) define the surface protein interactome between human microglia and mouse synapses in vivo, 2) co-transplant human microglia and human neurons in the mouse brain to explore human to human specific aspects of this interaction, and 3) investigate the human microglia specific secretome in AD.

This project will be the first of its kind to directly study the role of human microglia in the AD brain at cellular and molecular levels, opening new avenues for the development of new therapeutics and biomarkers to tackle disease.