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 language | English |
|---|---|
| Pages (from-to) | 118-126 |
| Number of pages | 9 |
| Journal | Brain Research |
| Volume | 1644 |
| DOIs | |
| Publication status | Published - 1 Aug 2016 |
| Externally published | Yes |
Keywords
- Biomarker
- CADASIL
- Endostatin
- HTRA1
- Notch 3 mouse mutant
- Stroke
- Vascular smooth muscle
Cite this
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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 journal › Article › Research › peer-review
TY - JOUR
T1 - Blood biomarkers in a mouse model of CADASIL
AU - Primo, Vincent
AU - Graham, Mark
AU - Bigger-Allen, Alexander A.
AU - Chick, Joel M.
AU - Ospina, Carolina
AU - Quiroz, Yakeel T.
AU - Manent, Jan
AU - Gygi, Steven P.
AU - Lopera, Francisco
AU - D'Amore, Patricia A.
AU - Arboleda-Velasquez, Joseph F.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
KW - Biomarker
KW - CADASIL
KW - Endostatin
KW - HTRA1
KW - Notch 3 mouse mutant
KW - Stroke
KW - Vascular smooth muscle
UR - http://www.scopus.com/inward/record.url?scp=84969256369&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2016.05.008
DO - 10.1016/j.brainres.2016.05.008
M3 - Article
VL - 1644
SP - 118
EP - 126
JO - Brain Research
JF - Brain Research
SN - 0006-8993
ER -