PHAGO has generated and characterized more than 40 iPSC lines, that will be deposited in the EBiSC2 iPSC repository that are available to the scientific community. PHAGO has generated reporter cell lines for TREM2 and CD33, and showed its suitability for drug screening. PHAGO has shown that TREM2 is cleaved and shed at the extracellular part. PHAGO has demonstrated that the shed soluble wild-type sTREM2 blocks amyloid-β aggregation and neurotoxicity, whereas the Alzheimer's TREM2-R47H mutant increases Aβ aggregation. PHAGO showed that the deletion of Alzheimer's disease-associated CD33 in iPSC microglia resulted in an inflammatory human microglia phenotype. PHAGO demonstrated that human induced pluripotent stem cell-derived microglia-like cells harboring TREM2 missense mutations show specific deficits in phagocytosis and migration. PHAGO has established highly sensitive biomarkers for detecting soluble TREM2 in the CSF of patients and monitored the levels of sTREM2 in carriers with rare TREM2 variants in relation to levels of neurofilament light chain. PHAGO has contributed to elucidate the role of sialylation for regulation of microglial function and for protecting the brain against inflammatory age-related loss of neurons.
PHAGO partners filed two patent applications. Firstly, DZNE (Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. Munich, Germany) showed that antibodies against the stalk region of TREM2 can enhance the protective clearance function of microglia and might have possible future potential for a clinical application. Secondly, Life & Brain GmbH (Bonn, Germany) established an up-scalable technique for production of microglia-like/-precursor cells and macrophage cell using mesh macrocarriers.
To achieve this output, PHAGO had regularly project discussion through reports, teleconferences within and between work packages and remote meetings via videoconferences. In total, six General Assembly Meetings have been organized to discuss the status of the project within the whole consortium.
