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Inflammation and AD: modulating microglia function focussing on TREM2 and CD33 - Sofia ref.: 115976

Periodic Reporting for period 3 - PHAGO (Inflammation and AD: modulating microglia function focussing on TREM2 and CD33 - Sofia ref.: 115976)

Reporting period: 2018-11-01 to 2019-10-31

Alzheimer’s disease (AD) is an age-related chronic neurodegenerative disease with progressive loss of nerve cells and their connectivity in the brain. Today, over 46 million people live with dementia worldwide and this number is estimated to increase to 131.5 million by 2050.

Phagocytes accumulate around amyloid plaques in the brains of AD patients and show a dysfunctional activation profile. Recent systems biology approaches have identified two innate immune receptor genes TREM2 and CD33/SIGLEC3 as disease relevant players in AD. These findings present novel and attractive targets for treatment. However, their exact role and underlying cellular mechanisms are still unclear.

PHAGO aims to fill this knowledge gap and provide tools and assays for targeting these innate immune receptors, namely TREM2 and CD33/SIGLEC3, to pave the way for the future development of drugs that delay the progression of Alzheimer’s disease. To achieve this, PHAGO brings together experts from industry and academia in a powerful collaboration.

Furthermore, and in order to deliver on objectives the PHAGO consortium is actively reaching out to other IMI-collaborative undertakings in order to maximally utilize synergisms throughout the European Research landscape. In the last project period, PHAGO signed two collaboration agreements: with (1) IMI ADAPTED (www.imi-adapted.eu) to join bioinformatics expertise and data related to the analyses of cell lines including iPSCs, patient samples, and animal models and (2) with IMI IMPRiND (www.imprind.org)to efficiently progress the work package dedicated to the analyses of animal models of tauopathy PHAGO. PHAGO also signed a Memorandum of Understanding with the IMI-imitative NEURONET (www.imi-neuronet.org) to increase the outreach about Neurodegeneration Diseases.
PHAGO has regularly project discussion through biannual reports, teleconferences within and between work packages and face-to-face meetings. In total, four General Assembly Meeting have been organized to discuss the status of the project with the whole consortium. In April 2019 PHAGO had a very successful Interim Review Meeting, organized by the IMI with an external Review Panel.

PHAGO is close to having generated and characterized more than 40 iPSC lines. The iPSC lines will be deposited at EBiSC and will be available in the course of the project to the scientific community. Further, partner Life & Brain has established an up-scalable technique for high yield production of iPSC-derived microglia that is amenable to bioreactor formats. Furthermore, the PHAGO partners have established harmonized protocols at different partner sites for differentiation of microglia out of iPSC.

PHAGO was able to identify Galactin-3 as a novel endogenous TREM2 ligand, which is upregulated in AD patients and is specifically associated with Aβ plaques.
• Boza-Serrano A. et al, 2019 Acta Neuropathol. (DOI: 10.1007/s00401-019-02013-z )

The CD33/SIGLEC3 crystal structure was published in the last PHAGO period and an already published small molecule CD33-binder was characterized, that under certain experimental conditions was able to increase the uptake of Aβ into microglia cells.
• Miles et al., 2019, iSCIENCE (/doi.org/10.1016/j.isci.2019.07.023)

PHAGO has further developed the knowledge platform, which focuses on knowledge and omics data from PHAGO partners and is being enriched by literature and omics data from 17 public resources. PHAGO harmonized public and own resources into a common language to get an overarching transcriptome fingerprint of human microglia.

PHAGO analyzed brains of 24-months old TREM2 KO mice and showed decreased age-related neuronal loss in parts of the brain. Further transcriptomic analyses reveal 200 differentially expressed genes.
• Linnartz-Gerlach B et al., 2018 Glia (doi.org/10.1002/glia.23563 )

Overall, PHAGO is well within its established work plan.
PHAGO has made several steps forward. PHAGO has generated iPSC and characterized microglial cells from iPSC lines. The iPSC will be deposited at EBiSC to be accessible for the scientific community. Furthermore, PHAGO continues to collect transcriptome data from partners and is further developing the knowledge platform focussed on omics-related data.
Schematic assay principal for screening TREM2-activating ligands with a cellular system.