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D Galimberti1, R Bonsi1, C Fenoglio1
1Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.
Abstract:
Mutations in progranulin gene (GRN) are one of the major causes of autosomal dominant Frontotemporal Lobar Degeneration (FTLD). Progranulin displays anti-inflammatory properties and is likely a ligand of Tumor Necrosis Factor (TNF) receptor 2, expressed on microglia. A few cytokines and chemokines are altered in cerebrospinal fluid (CSF) from patients with sporadic FTLD, whereas no information is available in familial cases. We evaluated, through BioPlex, levels of 27 inflammatory molecules, including cytokines, chemokines, and related receptors, in CSF and matched serum, from FTLD patients carrying GRN mutations as compared with sporadic FTLD with no GRN mutations and controls. Mean±SD Monocyte Chemoattractant Protein-1 (MCP-1) levels were significantly increased in CSF from sporadic FTLD patients as compared with controls (334.27±151.5 versus 159.7±49pg/ml; P⩽0.05). In GRN mutation carriers versus controls, CSF levels of MCP-1 were unchanged, whereas Interferon-γ-inducible protein-10 (IP-10) levels were increased (809.17±240.0 versus 436.61±202.5pg/ml; P=0.012). In the same group, TNFα and Interleukin (IL)-15 levels were decreased (3.18±1.41 versus 35.68±30.5pg/ml; P=0.013 and 9.34±5.54 versus 19.15±10.03pg/ml; P=0.023, respectively). Conversely, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) levels were decreased in patients, with or without mutations, as compared with controls (4.63±3.30 and 2.58±20 versus 87.57±70pg/ml, respectively; P<0.05). Moreover, IP-10, IL-15 and RANTES CSF levels were not influenced by age, whereas MCP-1 levels increased with age (ρ=0.48; P=0.007). In conclusion, inflammatory de-regulation was observed in both sporadic FTLD and GRN carriers compared to controls, with a specific inflammatory profile for the latter group.
Insights
Frontotemporal Lobar Degeneration (FTLD) involves altered inflammatory molecules in cerebrospinal fluid (CSF). GRN mutation carriers show increased Interferon-γ-inducible protein-10 (IP-10) and decreased Tumor Necrosis Factor-alpha (TNFα) and Interleukin-15 (IL-15) in CSF.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Mutations in the progranulin gene (GRN) are a primary cause of autosomal dominant Frontotemporal Lobar Degeneration (FTLD).
- Progranulin has anti-inflammatory roles and interacts with Tumor Necrosis Factor (TNF) receptor 2 on microglia.
- Previous studies noted altered cytokines/chemokines in sporadic FTLD CSF, but familial cases lacked data.
Purpose of the Study:
- To investigate inflammatory molecule profiles in cerebrospinal fluid (CSF) and serum of FTLD patients with GRN mutations.
- To compare these profiles with sporadic FTLD patients lacking GRN mutations and healthy controls.
- To identify specific inflammatory signatures associated with GRN mutations in FTLD.
Main Methods:
- BioPlex assay was used to quantify 27 inflammatory molecules (cytokines, chemokines, receptors) in CSF and serum.
- Samples were collected from FTLD patients with GRN mutations, sporadic FTLD patients, and controls.
- Statistical analyses were performed to compare molecule levels between groups and assess age-related changes.
Main Results:
- Sporadic FTLD patients showed significantly increased Monocyte Chemoattractant Protein-1 (MCP-1) in CSF compared to controls.
- GRN mutation carriers had elevated CSF levels of Interferon-γ-inducible protein-10 (IP-10) but decreased Tumor Necrosis Factor-alpha (TNFα) and Interleukin-15 (IL-15) compared to controls.
- Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) levels were decreased in both FTLD groups versus controls; MCP-1 levels correlated positively with age.
Conclusions:
- FTLD, both sporadic and GRN-mutation-related, exhibits inflammatory dysregulation compared to controls.
- GRN mutation carriers display a distinct inflammatory profile in CSF.
- Specific inflammatory markers like IP-10, TNFα, IL-15, and RANTES may serve as biomarkers for FTLD subtypes.
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