{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:03:24Z","timestamp":1789578204618,"version":"build-2803163510"},"reference-count":86,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministery of Science and Technology","award":["RYC-2006-002658"],"award-info":[{"award-number":["RYC-2006-002658"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Frontotemporal lobar degeneration (FTD) and Alzheimer\u2019s disease (AD) are proteinopathies characterized by the abnormal accumulation and aggregation of specific proteins like A\u03b2-42 deposits, p-tau accumulation, and abnormal cytosolic aggregation of TAR DNA-binding protein 43 (TDP-43) in FTD patients. Recently, the identification of neuroinflammatory mediators as predictors of cognitive decline has gained attention. We have compared several plasma biomarkers of cognitive impairment between AD and FTD patients using Enzyme-Linked Immunosorbent Assay (ELISA) (pg\/mL), including CX3CR1 and soluble fractalkine (sFK, also termed CX3CL1), TDP-43, neurofilament light chain M (NfL M), p-tau217, and GFAP (glial fibrillary acidic protein). Chemokines are HIV-1 co-receptors that facilitate the spread of HIV-1 infection and induce apoptosis in the brain. Whilst these chemokines promote neuronal survival and regulate neuron-glia interactions, they also contribute to neurodegeneration. Fractalkine, also known as CX3CL1, is a delta chemokine that binds to its CX3CR1 chemokine receptor. As a membrane isoform, fractalkine can be released in a soluble form by damaged neurons under either inflammatory and\/or excitotoxic conditions; since neuroinflammation contributes to neurodegeneration and dementia, we compared these CX3CR1\/sFK delta chemokine levels in seropositive patients (with suppressed viral loads) and without neurodegeneration to age-matched controls. This was done in order to study whether inflammation could upregulate these chemokines in the absence of cognitive impairment. To our knowledge, this is the first study showing that increased plasma levels of CX3CR1 and soluble fractalkine could be associated with FTD pathology as compared to control subjects (without neurodegeneration). However, peripheral NfL M, GFAP, and p-tau217 levels did not differ between AD and FTD patients. Post-mortem analysis of human FTD brains revealed anatomical changes, including hippocampal involution and tau deposits. Given that soluble fractalkine can contribute to cognitive impairment while also exerting protective effects against brain insults, we did an additional (independent experiment) in cortical neurons in vitro under LPS-induced neurotoxicity. We confirmed that adding recombinant fractalkine for 24 h prevented lipopolysaccharide (LPS)-induced apoptosis in cortical neurons at 7 days in vitro (DIV); moreover, twenty-four hours after LPS treatment, sFK prevented neuronal apoptosis by decreasing caspase-3 activity and exerted neuroprotective effects against inflammation. Our findings suggest that fractalkine mitigates LPS-induced neuronal injury by limiting apoptosis and inflammatory responses. Furthermore, our findings suggest for the first time that elevated circulating sFK levels may indirectly be associated with FTD pathology as compared to healthy controls. However, sFK could also reflect compensatory protective responses to neuronal injury.<\/jats:p>","DOI":"10.3390\/life16091554","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:07:29Z","timestamp":1789574849000},"page":"1554","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative Analysis of Plasma Biomarkers of Alzheimer\u2019s Disease and Frontotemporal Dementia: The Dual Role of Soluble Fractalkine as a Biomarker of Frontotemporal Dementia and Its Neuroprotective Effects in Cortical Neurons \u201cIn Vitro\u201d"],"prefix":"10.3390","volume":"16","author":[{"given":"Jos\u00e9 Joaqu\u00edn","family":"Merino","sequence":"first","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Farmacognosia y Bot\u00e1nica, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain"},{"name":"Instituto Pluridisciplinar, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain"},{"name":"Grupo de Medicina Regenerativa, Instituto de Investigaci\u00f3n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Julio","family":"Rodr\u00edguez-Arellano","sequence":"additional","affiliation":[{"name":"Functional Neuroanatomy Group, IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain"},{"name":"Department of Neurosciences, Medical Faculty, University of the Basque Country (UPV\/EHU), 48009 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1157-5590","authenticated-orcid":false,"given":"Xavier","family":"Busquets","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cell Biomedicine, Department of Biology, Faculty of Medicine, University of the Balearic Islands, 07122 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5019-0434","authenticated-orcid":false,"given":"Ana I.","family":"Flores","sequence":"additional","affiliation":[{"name":"Grupo de Medicina Regenerativa, Instituto de Investigaci\u00f3n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2274-5949","authenticated-orcid":false,"given":"Adolfo","family":"Toledano","sequence":"additional","affiliation":[{"name":"Instituto Cajal, CSIC, 28002 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e70046","DOI":"10.1002\/jnr.70046","article-title":"Alzheimer\u2019s Disease and Frontotemporal Dementia: A Review of Pathophysiology and Therapeutic Approaches","volume":"103","author":"Kelliny","year":"2025","journal-title":"J. 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