Blood biomarkers in a mouse model of CADASIL

Vincent Primo, Mark Graham, Alexander A. Bigger-Allen, Joel M. Chick, Carolina Ospina, Yakeel T. Quiroz, Jan Manent, Steven P. Gygi, Francisco Lopera, Patricia A. D'Amore, Joseph F. Arboleda-Velasquez

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)118-126
Number of pages9
JournalBrain Research
Volume1644
DOIs
Publication statusPublished - 1 Aug 2016
Externally publishedYes

Keywords

  • Biomarker
  • CADASIL
  • Endostatin
  • HTRA1
  • Notch 3 mouse mutant
  • Stroke
  • Vascular smooth muscle

Cite this

Primo, V., Graham, M., Bigger-Allen, A. A., Chick, J. M., Ospina, C., Quiroz, Y. T., ... Arboleda-Velasquez, J. F. (2016). Blood biomarkers in a mouse model of CADASIL. Brain Research, 1644, 118-126. https://doi.org/10.1016/j.brainres.2016.05.008
Primo, Vincent ; Graham, Mark ; Bigger-Allen, Alexander A. ; Chick, Joel M. ; Ospina, Carolina ; Quiroz, Yakeel T. ; Manent, Jan ; Gygi, Steven P. ; Lopera, Francisco ; D'Amore, Patricia A. ; Arboleda-Velasquez, Joseph F. / Blood biomarkers in a mouse model of CADASIL. In: Brain Research. 2016 ; Vol. 1644. pp. 118-126.
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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.",
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Primo, V, Graham, M, Bigger-Allen, AA, Chick, JM, Ospina, C, Quiroz, YT, Manent, J, Gygi, SP, Lopera, F, D'Amore, PA & Arboleda-Velasquez, JF 2016, 'Blood biomarkers in a mouse model of CADASIL', Brain Research, vol. 1644, pp. 118-126. https://doi.org/10.1016/j.brainres.2016.05.008

Blood biomarkers in a mouse model of CADASIL. / Primo, Vincent; Graham, Mark; Bigger-Allen, Alexander A.; Chick, Joel M.; Ospina, Carolina; Quiroz, Yakeel T.; Manent, Jan; Gygi, Steven P.; Lopera, Francisco; D'Amore, Patricia A.; Arboleda-Velasquez, Joseph F.

In: Brain Research, Vol. 1644, 01.08.2016, p. 118-126.

Research output: Contribution to journalArticleResearchpeer-review

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Primo V, Graham M, Bigger-Allen AA, Chick JM, Ospina C, Quiroz YT et al. Blood biomarkers in a mouse model of CADASIL. Brain Research. 2016 Aug 1;1644:118-126. https://doi.org/10.1016/j.brainres.2016.05.008