Long Name Inflammation and AD: modulating microglia function - focussing on TREM2 and CD33
Description Inflammation and AD: modulating microglia function - focussing on TREM2 and CD33. Clumps of proteins in the brain called amyloid plaques are a hallmark of Alzheimer’s disease, and very often specialised immune cells cluster around these plaques. Recent research has shown that two genes involved in the immune system, TREM2 and CD33, appear to be involved in this immune response to Alzheimer’s disease and could therefore be targets for drugs. However, their exact role in the disease is still poorly understood. The PHAGO project aims to develop tools and methods to study the workings of these genes. The project results will therefore pave the way for the development of novel drugs that could tackle Alzheimer’s disease via this route.
Objectives 1. Bring together scientific knowledge from different technical fields on TREM2 and CD33. 2. Allow rapid transfer of novel academic scientific findings on TREM2 and CD33 and related targets towards pharmaceutical and industrial research use. 3. Acquire key knowledge on the role of TREM2/CD33 in AD, including the development of validated assays, and identification of tool compounds and/or tool antibodies targeted to TREM2/CD33 and related target functions. 4. Generate innovative tools for investigating TREM2/CD33 and related pathways that are suitable for pharmaceutical and industrial research use. 5. Generate new knowledge regarding TREM2/CD33 and neuroinflammation to increase the competitiveness of European SMEs and pharmaceutical companies. 6. Disseminate and enable exploitation of the generated knowledge to relevant stakeholders for further development, including by the creation of a knowledge database containing data generated in this action.
Start date 01-11-2016
End date 01-04-2022
Name Projects Type of institution Country  
Sanofi-Aventis Recherche & Developpement EPAD EQIPD AETIONOMY IM2PACT PHAGO NEURONET Mobilise-D IDEA-FAST EPND EFPIA France
Fraunhofer Gesellschaft Zur Foerderung Der Angewandten Forschung EV EPAD AETIONOMY PHAGO RADAR-AD Academia Germany
Abbvie Deutschland GMBH & Co Kg ADAPTED PHAGO EFPIA Germany
Astrazeneca AB MOPEAD PHAGO Mobilise-D IDEA-FAST PD-MIND Pharma-Cog EFPIA Sweden
Charite - Universitaetsmedizin Berlin EQIPD PHAGO RADAR-CNS Academia Germany
Deutsches Zentrum Fur Neurodegenerative Erkrankungen Ev IMPRiND PD-MitoQUANT PHAGO EPND Academia Germany
Goeteborgs Universitet PHAGO ROADMAP EMIF EPND Academia Sweden
King's College London PHAGO RADAR-CNS RADAR-AD EMIF PD-MIND EPND Academia United Kingdom
Universitaetsklinikum Bonn AETIONOMY ADAPTED PHAGO Academia Germany
University College London AMYPAD PD-MitoQUANT PHAGO EMIF Academia United Kingdom
University Of Cambridge EPAD IMPRiND PHAGO EMIF IDEA-FAST Academia United Kingdom
Arttic PHAGO SME France
Axxam SA PHAGO SME Italy
Life And Brain Gmbh PHAGO SME Germany
Eisai Inc EPAD PHAGO Pharma-Cog EFPIA United States
WP number Description Project  
WP1 Project management, communication and dissemination PHAGO
WP2 Pathways, ligands, signaling PHAGO
WP3 In vitro and in vivo models of AD-related neuro-inflammation PHAGO
WP4 Identification of small and/or large molecule modulators PHAGO
WP5 Data and knowledge management PHAGO
Deliverable number Title Project Submission date Link Keywords  
D5.1 A comprehensive roadmap for data and knowledge management for the PHAGO consortium, collection of pre-existing ethical documents PHAGO 27-04-2017
D2.8 Knowledge of possible disease mechanisms and targets PHAGO 21-01-2020
D4.6 Crystal structure of CD33 generated to ~3 Å and refined to ~2 Å PHAGO 19-12-2019
D2.13 Determination of the cleavage site PHAGO 27-01-2017
D1.1 Press release containing a common part and a part that can be personalised by every partner PHAGO 11-01-2017
D1.2 Launch of website, Twitter and other dissemination activities PHAGO 19-04-2017
D2.21 CD33 receptor ligands characterization in human primary monocytes PHAGO 09-01-2020
D3.13 Providing existing RNAseq signatures and cytokine/chemokine signatures of microglia from tg4510 (tau) mice at various time points PHAGO 04-10-2017
D2.26 Completion of the analysis of changes in the glycosylation of TREM2 ectodomains in the presence of R47H variant PHAGO 19-11-2018
D2.28 map the cleavage sites on TREM2 ectodomains in the presence/absence of the R47H variant PHAGO 11-02-2020
D4.05 Crystal structure of TREM2 generated to at least 2-3 Å PHAGO 04-03-2020
Title First author last name Year Project Link Keywords  
TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant Thornton 2017 PHAGO Basic science research paper, TREM2, Alzheimer's disease, inflammation, myeloid cells
An Alzheimer associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function Schlepckow 2017 PHAGO Basic science research paper, TREM2, inflammation, microglia, Alzheimer's disease
Loss of Trem2 in microglia leads to widespread disruption of cell co-expression networks in mouse brain Carbajosa 2018 PHAGO Basic science research paper, TREM2, Alzheimer's disease, inflammation, RNA-Seq, Knockout mouse model, Endothelial cells
Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis Garcia-Reitboeck 2018 PHAGO Basic science research paper, induced pluripotent stem cells (iPSC), microglia, TREM2, phagocytosis, inflammation, Nasu-Hakola disease, Alzheimer disease
The Trem2 R47H Alzheimer’s risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans Xiang 2018 PHAGO Basic science research paper, clinical research, Alzheimer’s disease, Microglia, inflammation, Neurodegeneration, TREM2, Pre-mRNA splicing, microglia
Effective Knockdown of Gene Expression in Primary Microglia With siRNA and Magnetic Nanoparticles Without Cell Death or Inflammation Carrillo-Jimenez 2018 PHAGO Basic science research paper, microglia, inflammation, siRNA, transfection, TREM2, CD33, Alzheimer’s disease
Loss of Function of TREM2 Results in Cytoskeletal Malfunction in Microglia Phillips 2018 PHAGO Basic science research paper, inflammation, microglia, Nasu-Hakola disease, Dementia, TREM2
Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE Parhizkar 2019 PHAGO Basic science research paper, TREM2, ApoE, Amyloid, Alzheimer's disease, mouse model, PET imaging
TREM2 triggers microglial density and age-related neuronal loss Linnartz-Gerlach 2019 PHAGO Basic science research paper, TREM2, microglia, inflammation, mouse model, aging
Small Molecule Binding to Alzheimer’s Risk Factor CD33 Promotes Aβ Phagocytosis Luke 2019 PHAGO Basic science research paper, CD33, amyloid, Alzheimer's disease, inflammation
Enhancing Protective Microglial Activities With a Dual Function TREM2 Antibody to the Stalk Region Schlepckow 2020 PHAGO Basic research paper, Alzheimer's disease, TREM2, amyloid β-peptide, microglia, therapeutic antibody
Lipopolysaccharide activates microglia via neuraminidase 1 desialylation of Toll‐like Receptor 4 Allendorf 2020 PHAGO Basic research paper, microglia, inflammation, in vitro, sialic acid
A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia Piers 2019 PHAGO Alzheimer´s disease, glycolysis, metabolism, microglia
A rare heterozygous TREM2 coding variant identifiedin familial clustering of dementia affects an intrinsicallydisordered protein region and function of TREM2 Karsak 2019 PHAGO Alzheimer´s disease, conformation, dementia, intrinsically disordered region, TREM2
Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease Boza-Serrano 2019 PHAGO Alzheimer’s disease (AD), Galectin-3, TREM2, Microglia, Inflammation, Amyloid aggregation
Sialylation acts as a checkpoint for innate immune responses in the central nervous system Klaus 2020 PHAGO complement system, desialylation, microglia, neuraminidases, sialic acid, SIGLEC
Sialylation and Galectin-3 in Microglia-Mediated Neuroinflammation and Neurodegeneration Puigdellívol 2020 PHAGO sialic acid, desialylation, galectin-3, phagocytosis, microglia, neurodegeneration, aging
Interleukin‐12/23 deficiency differentially affects pathology in male and female Alzheimer's disease‐like mice Eede 2020 PHAGO Alzheimer's disease, gender, IL‐12/IL‐23, innate immunity, β‐amyloid,
Plasma levels of soluble TREM2 and neurofilament light chain in TREM2 rare variant carriers Ashton 2018 PHAGO Alzheimer’s disease, sTREM2, Blood, Biomarkers, Neurofilament light chain
Activated microglia desialylate their surface, stimulating complement receptor 3‐mediated phagocytosis of neurons Allendorf 2019 PHAGO complement receptor 3, desialylation, inflammation, microglia, neuraminidase, neurodegeneration, phagocytosis,
Deletion of Alzheimer's disease-associated CD33 results in an inflammatory human microglia phenotype Wißfeld 2021 PHAGO Alzheimer's disease, CD33 (sialic-acid-binding immunoglobulin-like lectin 3 [SIGLEC3]), microglia, neuroinflammation, oxidative burst, phagocytosis, protein tyrosine phosphatase, non-receptor type 6 (PTPN6)
Reporter cell assay for human CD33 validated by specific antibodies and human iPSC-derived microglia Wißfeld 2021 PHAGO antibody, cell, phosphorylation, signaling, calcium, receptor, activation
Differential interaction with TREM2 modulates microglial uptake of modified Aβ species Joshi 2021 PHAGO Alzheimer's disease; FTD mutation; TREM2; amyloid β; phosphorylation; post-translational modification.
TREM2 modulates differential deposition of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits Joshi 2021 PHAGO TREM2, Microglia, Post-translational modification, Aβ, Intraneuronal, Vascular deposits
Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons Mallach 2021 PHAGO Alzheimer’s disease; dementia; exosomes; intercellular signalling; microglia; proteome.
A reporter cell system for the triggering receptor expressed on myeloid cells 2 reveals differential effects of disease-associated variants on receptor signaling Ibach 2020 PHAGO TREM2 variants; agonistic antibody; reporter system; signaling.
Microglial phagocytosis of neurons in neurodegeneration, and its regulation Butler 2021 PHAGO Alzheimer's disease; Parkinson's disease; ageing; microglia; neurodegeneration; neuroinflammation; phagocytosis.
CD33M inhibits microglial phagocytosis, migration and proliferation, but the Alzheimer’s disease-protective variant CD33m stimulates phagocytosis and proliferation, and inhibits adhesion Butler 2021 PHAGO Alzheimer's disease; CD33; Microglia; Neuroinflammation; Siglec-3.
Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation Vilalta 2021 PHAGO Alzheimer's disease; TREM2; amyloid beta; microglia; neurotoxicity; oligomers; sTREM2.
The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles Mallach 2021 PHAGO Alzheimer’s disease; TREM2; exosomes; microglia.
Title Description Type Project  
Neuroimaging data from the KCL neuroimaging study

PHAGO will perform prospective human clinical Positron Emission Tomography (PET) scanning of neuroinflammation in a very small group (MMSE=20) with/ without TREM2 R47H alleles (at KCL). For more information please visit:

dataset-clinical-phago-12 PHAGO
CSF samples from the TREM2 variant cohort of KCL

PHAGO will search for novel microglia related biomarkers in the CSF of AD patients using advanced mass spectrometry technologies for allowing a better monitoring of potential therapies. Samples will be obtained from participants in the TREM2 variant cohort (R47H) at KCL. For more information please visit:

biological-samples-clinical-phago-7 PHAGO
Biomedical Knowledge Miner from Fraunhofer

The Biomedical Knowledge Miner (BiK>Mi) provides tools to access and validate knowledge encompassing all of the latest information pertaining to Alzheimer's Disease. This project aims to use a comprehensive computational model of biological mechanisms in the context of Alzheimer's Disease to determine currently used drugs that can effectively treat this disease. This drug repurposing workflow would significantly expedite development and research time as well as be applied to a variety of diseases.

platform-non-clinical-phago-12 PHAGO
Tools and assays for targeting and analysing TREM2 & CD33

PHAGO will generate TREM2 and CD33 tools for use to the research community. These tools will include reporter cells and optimised reporter assays, suitable for further development of treatments targeting TREM2 and/or CD33 in AD. Furthermore, PHAGO will generate several iPSC lines with TREM2 and CD33 variants. For more information, please see:

tools-non-clinical-phago-15 PHAGO
TREM2 cleavage modulators and uses thereof

This asset relates to a binding molecule having a binding site within the ectodomain of the triggering receptor expressed on myeloid cells 2 (TREM2), wherein the binding molecule inhibits TREM2 cleavage. This binding molecule is particularly useful for treating and/or preventing a neurological disorder, such as a neurodegenerative disorder. Also encompassed by this asset is a pharmaceutical composition for use in treating and/or preventing a neurological disorder, wherein the pharmaceutical composition comprises the binding molecule of the asset.

Neurodegenerative disorders that may be treated and/or prevented by using the binding molecule of this asset include Alzheimer's disease (AD), Frontotemporal lobar degeneration (FTLD), FTLD-like syndrome, Parkinson's disease, Nasu-Hakola disease, Multiple sclerosis (MS), Huntington disease, immune-mediated neuropathies, or Amyotrophic lateral sclerosis (ALS).

tools-non-clinical-phago-29 PHAGO


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