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

Title Deciphering the microglia-neuron interactions in human Alzheimer’s disease
Acronym XenoMicrogliaAD
Start date 2022-09-01
End date 2027-08-31
Sponsor European Research Council - Starting Grant (ERC-StG)
Institution VIB - Center for Molecular Neurology

Associated cell lines

Project Description

Microglia are one of the central players in the pathogenesis of Alzheimer’s disease (AD). Despite intense efforts in characterizing the transcriptomic and epigenetic response of microglia in AD, it is yet to be defined how they communicate with other cells in the brain and by which mechanism they lead to neuronal alterations. My overall objective is to define the contribution of human microglia (hMG) to synaptic dysfunction and neurodegeneration in vivo. There are crucial differences between human and mouse microglia, especially in terms of expression of specific AD linked genes, which highlight the necessity of working in human systems. Additionally, many aspects of the biology of these cells cannot be easily studied in vitro – for example complex interactions with other cell types. I will use a novel hMG xenotransplantation model that I established myself, and study two of the main functional aspects by which microglia can contribute to the neuropathology – synaptic elimination and release of soluble inflammatory factors that cause neuronal dysfunction or degeneration. I will apply cutting-edge proximity and metabolic labelling strategies (TurboID) combined with my xenotransplantation model to decipher the precise interactions between hMG and neurons, as well as the complexity of the microglial secretome in AD. I will 1) Map the landscape of the microglia-synapse interactions in the healthy and AD brain, using my hMG xenotransplantation model and proximity labelling. 2) Decipher the molecular interactome of hMG and human neurons in AD in vivo, by co-transplanting hMG and neurons and determining their surface interactome. 3) Determine the hMG specific secretome in AD by metabolic labelling of all proteins produced by the transplanted hMG. This project will be the first of its kind to directly study the role of hMG in the AD brain at cellular and molecular levels, opening new avenues for the development of new therapeutics and biomarkers to tackle disease.