title: Blood biomarkers in a mouse model of CADASIL.
abstract: Mutations in NOTCH 3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a neurological disorder characterized by stroke, and vascular cognitive impairment and dementia. Loss of vascular smooth muscle cells (VSMC) and accumulation of granular osmiophilic material (GOM) deposits are hallmarks of CADASIL. There are no therapies for CADASIL and experimental endpoints to examine the preclinical efficacy of potential drugs are lacking. This study aims to use a mouse carrying the C455R mutation in Notch 3 to identify biomarkers associated with CADASIL. Mass spectrometry and antibody arrays were used to explore the aorta and blood proteomes of CADASIL mice, ELISA assays were utilized for biomarker validation, a ligand-dependent assay was applied to examine the relationship between Notch signaling and biomarker expression, and retinal histology was performed for quantification of VSMC loss in arteries. Two-hundred day-old mice with the C455R CADASIL mutation in Notch 3 mice display robust VSMC loss in retinal arteries and had increased plasma levels of collagen18α1/endostatin (col18α1) and high-temperature requirement A serine peptidase 1 (HTRA1) and reduced levels of Notch 3 extracellular domain (N3ECD), compared to control wild type mice. Measurements of plasma endostatin, HTRA1 and N3ECD, along with VSMC quantification in retinal arteries, may serve as surrogate endpoints for assessing efficacy in preclinical therapeutic studies of CADASIL using mice.
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Primo
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Graham
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Bigger-Allen
authors.affiliation: Cell Biology Department, Harvard Medical School, Boston, MA, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Chick
authors.affiliation: Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ospina
authors.affiliation: Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia; Departments of Psychiatry and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Yakeel T
authors.initials: YT
authors.lastname: Quiroz
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia.
authors.forename: Jan
authors.initials: J
authors.lastname: Manent
authors.affiliation: Cell Biology Department, Harvard Medical School, Boston, MA, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Francisco
authors.initials: F
authors.lastname: Lopera
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA. Electronic address: patricia_damore@meei.harvard.edu.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: D'Amore
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. Electronic address: joseph_arboleda@meei.harvard.edu.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Arboleda-Velasquez
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D046589:CADASIL / Q000097:blood* / Q000175:diagnosis*; D004195:Disease Models, Animal; D043169:Endostatins / Q000097:blood; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D010641:Phenotype; D040901:Proteomics; D000071656:Receptor, Notch3 / Q000235:genetics*; D012161:Retinal Artery / Q000473:pathology; D012697:Serine Endopeptidases / Q000097:blood
chemical_list: D015415:Biomarkers; D043169:Endostatins; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D000074289:High-Temperature Requirement A Serine Peptidase 1; C492073:HtrA1 protein, mouse; D012697:Serine Endopeptidases
keywords: Biomarker; CADASIL; Endostatin; HTRA1; Notch 3 mouse mutant; Stroke; Vascular smooth muscle