YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias
Open accessAbstract
BACKGROUND: YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing. METHODS: In the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures. RESULTS: YKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer's disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around β-amyloid plaques, and surrounding vessels with β-amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology. CSF YKL-40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD (p < 0.001, AUC = 0.92) and AD (p < 0.001, AUC = 0.77) but not in vascular dementia (VaD) (p > 0.05, AUC = 0.71) or in DLB/Parkinson's disease dementia (PDD) (p > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP-D178N (Fatal Familial Insomnia) and PRNP-E200K mutations. CONCLUSIONS: Our results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component.
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Neuroinflammatory readouts such as soluble TREM2, YKL-40, or inflammasome-derived products may provide insight into the immune component of Alzheimer's disease progression.
“Neuroinflammatory readouts such as soluble TREM2, YKL-40, or inflammasome-derived products (e.g., caspase-1 cleavage fragments) may provide insight into the immune component of disease progression [172, 173].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [173]
The Discussion reports elevated YKL-40 in early Alzheimer’s disease and describes YKL-40 measurement as potentially useful for detecting early neuroinflammatory changes. It does not substantiate the sentence’s other examples—soluble TREM2 or inflammasome-derived products such as caspase-1 cleavage fragments—as readouts of disease progression. (LLM, conf=0.86)
Experimental — accuracy not yet measuredChil1/CHI3L1/YKL-40, the top hub gene in honeydew1, is related to inflammation and AD pathophysiology.
“Notably, Chil1/CHI3L1/YKL-40 (Chitinase-like 1) that is the top hub gene in honeydew1 is related to inflammation and AD pathophysiology [39].”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [39]
GFAP is highly upregulated in astrocytes upon disease.
“GFAP is highly upregulated in astrocytes upon disease [73,75,107].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [107]
Prion disease-associated astrogliosis is prominent in human prion diseases as shown by upregulation of GFAP and YKL-40 (CHI3L1).
“Prion disease-associated astrogliosis is also prominent in human prion diseases as shown by the upregulation of GFAP and YKL-40 (or Chitinase-3-like protein 1; CHI3L1) (Figure 6B) [73,107].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [107]
While GFAP increase is also found in other neurodegenerative diseases such as AD, YKL-40 upregulation is more specific for human CJD and might serve as a diagnostic marker.
“However, while a GFAP increase is also found in other neurodegenerative diseases such as AD [97], YKL-40 upregulation is more specific for human CJD and might serve as a diagnostic marker [107].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [107]
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Self-citation
- Authors
- Llorens, F., Thüne, K., Tahir, W., Kanata, E., Diaz-Lucena, D., Xanthopoulos, K., Kovatsi, E., Pleschka, C., Garcia-Esparcia, P., Schmitz, M., Ozbay, D., Correia, S., Correia, Â., Milosevic, I., Andréoletti, O., Fernández-Borges, N., Vorberg, I. M., Glatzel, M., Sklaviadis, T., Torres, J. M., Krasemann, S., Sánchez-Valle, R., Ferrer, I., & Zerr, I.
- Affiliations
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- German Center for Neurodegenerative Diseases (DE)
- Universitätsmedizin Göttingen (DE)
- Aristotle University of Thessaloniki (GR)
- École Nationale Vétérinaire de Toulouse (FR)
- University Medical Center Hamburg-Eppendorf (DE)
- Corresponding author
- Llorens, Franc
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2017-11-10
- Volume
- 12
- Issue
- 1
- Pages
- 83-83
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC5681777
- OpenAlex
- W2767733203
- Cited by
- 249
- References
- 107
- Citations by year
- 2026: 13 · 2025: 37 · 2024: 33 · 2023: 31 · 2022: 43 · 2021: 34 · 2020: 30 · 2019: 18 · 2018: 7 · 2017: 1
- FWCI
- 7.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion, cc-by)
- HAL (submittedVersion, cc-by)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-sa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- DZNE Pub (submittedVersion, other-oa)
- Funders
- Robert Koch Institute
- Ciberned (BESAD-P)
- Spanish Ministry of Health - Instituto Carlos III/Fondo Social Europeo (CP16/00041)
- MINECO (AGL2015-71764-REDT)
- DAAD - IKYDA (57260006)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- YKL-40, neurodegenerative dementia, cerebrospinal fluid biomarkers, sporadic Creutzfeldt-Jakob disease, Alzheimer's disease, dementia with Lewy bodies, prion disease, fatal familial insomnia, neuroinflammation, reactive astrocytes, amyloid plaques, vascular dementia, Parkinson's disease dementia
- MeSH terms
- Chitinase-3-Like Protein 1, Aged, Animals, Brain, Cerebrospinal Fluid, Dementia, Female, Humans, Male, Mice, Transgenic, Middle Aged, Biomarkers, Neurodegenerative Diseases, Mice
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