title: NF-L in cerebrospinal fluid and serum is a biomarker of neuronal damage in an inducible mouse model of neurodegeneration.
abstract: Accumulation of neurofilaments (NFs), the major constituents of the neuronal cytoskeleton, is a distinctive feature of neurological diseases and several studies have shown that soluble NFs can be detected in the cerebrospinal fluid (CSF) of patients with neurological diseases, such as multiple sclerosis and frontotemporal dementia. Here we have used an inducible transgenic mouse model of neurodegeneration, CamKII-TetOp25 mice, to evaluate whether NF-L levels in CSF or blood can be used as a biochemical biomarker of neurodegeneration. Induction of p25 transgene brain expression led to increase in CSF and serum NF-L levels that correlated with ongoing neurodegeneration. Switching off p25 prevented further increases in both CSF and serum NF-L levels and concomitantly stopped the progression of neurodegeneration. The levels of CSF NF-L detected in p25 mice are about 4-fold higher than the CSF levels detected in patients with chronic neurodegenerative diseases, such as symptomatic FTD (bvFTD). In addition, our data indicate that the NF-L detected in CSF is most likely a cleaved form of NF-L. These results suggest that CSF and serum NF-L are of interest to be further explored as potential translational dynamic biomarkers of neurodegeneration or as pharmacodynamics biomarkers at least in preclinical animal studies.
authors.affiliation: Sanofi R&D, Neuroscience Research Therapeutic Area, Neurodegeneration Cluster, 1 Avenue Pierre Brossolette, Chilly Mazarin, 91380, France; Pharnext, 11 rue des Peupliers, 92130 Issy-les-Moulineaux, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Brureau
authors.affiliation: Sanofi R&D, Translational Sciences Unit, Chilly Mazarin, 91380, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Blanchard-Bregeon
authors.affiliation: Evotec, 19 route d'Espagne, - BP13669-31036 Toulouse Cedex 1, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pech
authors.affiliation: Sanofi R&D, Translational Sciences Unit, Chilly Mazarin, 91380, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Hamon
authors.affiliation: Sanofi R&D, Translational Sciences Unit, Chilly Mazarin, 91380, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Chaillou
authors.affiliation: Sanofi R&D, Translational Sciences Unit, Chilly Mazarin, 91380, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Guillemot
authors.affiliation: Sanofi R&D, Neuroscience Research Therapeutic Area, Neurodegeneration Cluster, 1 Avenue Pierre Brossolette, Chilly Mazarin, 91380, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Barneoud
authors.affiliation: Sanofi R&D, Neuroscience Research Therapeutic Area, Neurodegeneration Cluster, 1 Avenue Pierre Brossolette, Chilly Mazarin, 91380, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertrand
authors.affiliation: Sanofi R&D, Neuroscience Research Therapeutic Area, Neurodegeneration Cluster, 1 Avenue Pierre Brossolette, Chilly Mazarin, 91380, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Pradier
authors.affiliation: Sanofi R&D, Neuroscience Research Therapeutic Area, Neurodegeneration Cluster, 1 Avenue Pierre Brossolette, Chilly Mazarin, 91380, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rooney
authors.affiliation: Sanofi R&D, Neuroscience Research Therapeutic Area, Neurodegeneration Cluster, 1 Avenue Pierre Brossolette, Chilly Mazarin, 91380, France. Electronic address: nathalie.schussler@sanofi.com.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schussler
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005452:Fluoresceins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000097:blood / Q000134:cerebrospinal fluid / Q000473:pathology; D016900:Neurofilament Proteins / Q000097:blood* / Q000134:cerebrospinal fluid*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D000072260:RNA Splicing Factors / Q000378:metabolism
chemical_list: C492236:Cdk5r1 protein, mouse; D005452:Fluoresceins; D016900:Neurofilament Proteins; D000072260:RNA Splicing Factors; C465036:Rbfox1 protein, mouse; C435731:fluoro jade; D049452:Green Fluorescent Proteins; D010770:Phosphotransferases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D010751:Phosphopyruvate Hydratase
keywords: Biomarker; Cerebrospinal fluid; Inducible p25 mice; Neurodegeneration; Neurofilament light chain