{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:01:23Z","timestamp":1768507283919,"version":"3.49.0"},"posted":{"date-parts":[[2023,6,18]]},"group-title":"Neuroscience","reference-count":83,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,6,16]]},"abstract":"<jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>With the emergence of microglia-modulating therapies there is an urgent need for reliable biomarkers to evaluate microglial activation states.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using mouse models and human induced pluripotent stem cell-derived microglia (hiMGL), which were genetically modified to yield the most opposite homeostatic (\n                      <jats:italic>TREM2-<\/jats:italic>\n                      knockout) and disease-associated (\n                      <jats:italic>GRN<\/jats:italic>\n                      -knockout) states, we identified microglia activity-dependent markers. Non-targeted mass spectrometry was used to identify changes in microglial and cerebrospinal (CSF) proteome of\n                      <jats:italic>Grn<\/jats:italic>\n                      - and\n                      <jats:italic>Trem2<\/jats:italic>\n                      -knockout mice. Additionally, we analyzed the proteome of\n                      <jats:italic>GRN<\/jats:italic>\n                      - and\n                      <jats:italic>TREM2<\/jats:italic>\n                      -knockout hiMGL and their conditioned media. Candidate marker proteins were tested in two independent patient cohorts, the ALLFTD cohort with 11\n                      <jats:italic>GRN<\/jats:italic>\n                      mutation carriers and 12 non-carriers, as well as the proteomic data set available from the European Medical Information Framework Alzheimer\u2019s Disease Multimodal Biomarker Discovery (EMIF-AD MBD).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>\n                      We identified proteomic changes between the opposite activation states in mouse microglia and cerebrospinal fluid (CSF), as well as in hiMGL cell lysates and conditioned media. For further verification, we analyzed the CSF proteome of heterozygous\n                      <jats:italic>GRN<\/jats:italic>\n                      mutation carriers suffering from frontotemporal dementia (FTD). We identified a panel of six proteins (FABP3, MDH1, GDI1, CAPG, CD44, GPNMB) as potential indicators for microglial activation. Moreover, we confirmed three of these proteins (FABP3, GDI1, MDH1) to be significantly elevated in the CSF of AD patients. In AD, these markers differentiated amyloid-positive cases with mild cognitive impairment (MCI) from amyloid-negative individuals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>The identified candidate proteins reflect microglia activity and may be relevant for monitoring the microglial response in clinical practice and clinical trials modulating microglial activity and amyloid deposition. Moreover, the finding that three of these markers differentiate amyloid-positive from amyloid-negative MCI cases in the AD cohort suggests that these marker proteins associate with a very early immune response to seeded amyloid. This is consistent with our previous findings in the DIAN (Dominantly Inherited Alzheimer\u2019s Disease Network) cohort, where soluble TREM2 increases as early as 21 years before symptom onset. Moreover, in mouse models for amyloidogenesis, seeding of amyloid is limited by physiologically active microglia further supporting their early protective role. The biological functions of some of our main candidates (FABP3, CD44, GPNMB) also further emphasize that lipid dysmetabolism may be a common feature of neurodegenerative disorders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Funding<\/jats:title>\n                    <jats:p>This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany\u2019s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy \u2013 ID 390857198 to CH, SFL and DP) and a Koselleck Project HA1737\/16-1 (to CH).<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.1101\/2023.06.15.545187","type":"posted-content","created":{"date-parts":[[2023,6,18]],"date-time":"2023-06-18T13:30:21Z","timestamp":1687095021000},"source":"Crossref","is-referenced-by-count":2,"title":["A MICROGLIAL ACTIVITY STATE BIOMARKER PANEL DIFFERENTIATES FTD-GRANULIN AND ALZHEIMER\u2019S DISEASE PATIENTS FROM CONTROLS"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3902-3137","authenticated-orcid":false,"given":"Ida","family":"Pes\u00e4maa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3414-307X","authenticated-orcid":false,"given":"Stephan A.","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1261-1370","authenticated-orcid":false,"given":"Sophie","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alana","family":"Darcher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2065-1639","authenticated-orcid":false,"given":"Dominik","family":"Paquet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2211-2575","authenticated-orcid":false,"given":"Stefan F.","family":"Lichtenthaler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4869-1627","authenticated-orcid":false,"given":"Christian","family":"Haass","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023062113051007000_2023.06.15.545187v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.10.015"},{"key":"2023062113051007000_2023.06.15.545187v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.003"},{"issue":"5","key":"2023062113051007000_2023.06.15.545187v1.3","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.neuron.2020.09.029","article-title":"Emerging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer\u2019s Disease","volume":"108","year":"2020","journal-title":"Neuron"},{"key":"2023062113051007000_2023.06.15.545187v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0072-1"},{"key":"2023062113051007000_2023.06.15.545187v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3009093"},{"key":"2023062113051007000_2023.06.15.545187v1.6","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aag1767"},{"issue":"4","key":"2023062113051007000_2023.06.15.545187v1.7","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S1474-4422(22)00027-8","article-title":"Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer\u2019s disease: a longitudinal observational study","volume":"21","year":"2022","journal-title":"Lancet Neurol"},{"key":"2023062113051007000_2023.06.15.545187v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0296-9"},{"key":"2023062113051007000_2023.06.15.545187v1.9","doi-asserted-by":"crossref","unstructured":"Ewers M , Franzmeier N , Suarez-Calvet M , Morenas-Rodriguez E , Caballero MAA , Kleinberger G , et al. 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