Valerie L. Sim, José Eriton Gomes da Cunha, Niels Kruse, Óscar López-Pérez, Katrin Thüne, Enric Vidal, Peter Hermann, Inga Zerr, Miguel Calero, Henrik Zetterberg, Daniela Diaz-Lucena, Matthias Schmitz, Anna Villar-Piqué, Franc Llorens, Hailey Pineau, Alba Marín-Moreno, Raquel Sánchez-Valle, Joachim Riggert, José Antonio del Río, Kaj Blennow, Pol Andrés-Benito, Juan María Torres, Isidre Ferrer, Brit Mollenhauer, Anna Ladogana, Juan Carlos Espinosa, Generalitat de Catalunya, Instituto de Salud Carlos III, Fundació La Marató de TV3, European Commission, Swedish Research Council, Ministero della Salute, Alzheimer Society of Canada, Ministerio de Ciencia, Innovación y Universidades (España), Diaz-Lucena, Daniela, Kruse, Niels, Thüne, Katrin, Villar-Piqué, Anna, da Cunha, Jose Eriton Gomes, López-Pérez, Óscar, Andrés-Benito, Pol, Ladogana, Anna, Calero, Miguel, Vidal, Enric, Pineau, Hailey, Sim, Valerie, Zetterberg, Henrik, Blennow, Kaj, Del Río, Jose Antonio, Marín-Moreno, Alba, Espinosa, Juan Carlos, Torres, Juan María, Sánchez-Valle, Raquel, Mollenhauer, Brit, Ferrer, Isidre, Zerr, Inga, Producció Animal, Sanitat Animal, Government of Catalonia (España), Fundación La Marató TV3, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Unión Europea. Comisión Europea. H2020, European Research Council, Alzheimers Drug Discovery Foundation, UK Dementia Research Institute, Stichting Alzheimer Onderzoek, Hjärnfonden (Suecia), Swedish government, European Union Joint Programme for Neurodegenerative Disorders, Ministero della Salute (Italia), Alberta Synergies in Alzheimer’s and Related Disorders, Alzheimer Society of Alberta and Northwest Territories, and Centro de Investigación Biomédica en Red - CIBERNED (Enfermedades Neurodegenerativas)
19 Pág. Centro de Investigación en Sanidad Animal (CISA), Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune cell surface receptor that regulates microglial function and is involved in the pathophysiology of several neurodegenerative diseases. Its soluble form (sTREM2) results from shedding of the TREM2 ectodomain. The role of TREM2 in prion diseases, a group of rapidly progressive dementias remains to be elucidated. In the present study, we analysed the expression of TREM2 and its main sheddase ADAM10 in the brain of sporadic Creutzfeldt-Jakob disease (sCJD) patients and evaluated the role of CSF and plasma sTREM2 as a potential diagnostic marker of prion disease. Our data indicate that, compared to controls, TREM2 is increased in sCJD patient brains at the mRNA and protein levels in a regional and subtype dependent fashion, and expressed in a subpopulation of microglia. In contrast, ADAM10 is increased at the protein, but not the mRNA level, with a restricted neuronal expression. Elevated CSF sTREM2 is found in sCJD, genetic CJD with mutations E200K and V210I in the prion protein gene (PRNP), and iatrogenic CJD, as compared to healthy controls (HC) (AUC = 0.78-0.90) and neurological controls (AUC = 0.73-0.85), while CSF sTREM2 is unchanged in fatal familial insomnia. sTREM2 in the CSF of cases with Alzheimer's disease, and multiple sclerosis was not significantly altered in our series. CSF sTREM2 concentrations in sCJD are PRNP codon 129 and subtype-related, correlate with CSF 14-3-3 positivity, total-tau and YKL-40, and increase with disease progression. In plasma, sTREM2 is increased in sCJD compared with HC (AUC = 0.80), displaying positive correlations with plasma total-tau, neurofilament light, and YKL-40. We conclude that comparative study of TREM2 in brain and biological fluids of prion diseases reveals TREM2 to be altered in human prion diseases with a potential value in target engagement, patient stratification, and disease monitoring., We thank the HUB-ICO-IDIBELL-Biobank and the CERCA Programme of the Generalitat de Catalunya for institutional support. This study was funded by the Instituto Carlos III (Grants Number CP16/00041 and PI19/00144) to FL. This project was also funded by la Fundació La Marató de TV3 (Grants No. 201821-30, 201821-31and 201821-32 to FL, JCE and EV, respectively) and by the Fondo Europeo de Desarrollo Regional (FEDER) through the Interreg V-A España-Francia-Andorra (POCTEFA 2014–2020) programme (at 65%) to IF. AVP is supported by the Beatriu de Pinós programme (2018-BP-00129) from the Ministry of Business and nowledge of the Government of Catalonia, and cofunded by the EU Horizon 2020 programme under an MSCA grant agreement (801370). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915), the Swedish State Support for Clinical Research (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and the European Union Joint Programme for Neurodegenerative Disorders (JPND2019-466-236). AL is supported by the Ministero della Salute, Italy, for the national surveillance of Creutzfeldt-Jakob disease. This research was also supported in part by the Alberta Synergies in Alzheimer’s and Related Disorders (SynAD) programme which is funded by the Alzheimer Society of Alberta and Northwest Territories through their Hope for Tomorrow programme and the University Hospital Foundation. SynAD operates in partnership with the Neuroscience and Mental Health Institute at the University of Alberta. JADR was supported by grants from the Spanish Ministry of Science, Innovation and Universities (MICINN/FEDER) (RTI2018-099773-B-I00), the CERCA Programme, and by the Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya (SGR2017-648) and CIBERNED (CMED2018-2)