Related Experiment Video
Updated: Mar 21, 2026
Evaluation of a Reliable Biomarker in a Cecal Ligation and Puncture-Induced Mouse Model of Sepsis
Published on: December 9, 2022
Blood biomarkers in a mouse model of CADASIL
Vincent Primo1, Mark Graham1, Alexander A Bigger-Allen1
1Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Insights
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological disorder with no current therapies. This study identified novel biomarkers, including endostatin and HTRA1, in CADASIL mice, offering potential surrogate endpoints for future drug development.
Area of Science:
- Neuroscience
- Genetics
- Vascular Biology
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic neurological disorder caused by NOTCH3 mutations.
- Hallmarks include vascular smooth muscle cell (VSMC) loss and granular osmiophilic material (GOM) deposition, leading to stroke and cognitive decline.
- Current lack of therapies necessitates the development of preclinical models and surrogate endpoints for drug efficacy assessment.
Purpose of the Study:
- To identify potential biomarkers for CADASIL using a mouse model with a Notch 3 C455R mutation.
- To evaluate these biomarkers as surrogate endpoints for preclinical therapeutic studies.
Main Methods:
- Proteomic analysis (mass spectrometry, antibody arrays) of aorta and blood from CADASIL mice.
- ELISA assays for biomarker validation.
- Ligand-dependent assays to assess Notch signaling.
- Retinal histology to quantify VSMC loss.
Main Results:
- CADASIL mice exhibited significant VSMC loss in retinal arteries.
- Elevated plasma levels of collagen18α1/endostatin (col18α1) and high-temperature requirement A serine peptidase 1 (HTRA1) were observed.
- Reduced levels of Notch 3 extracellular domain (N3ECD) were detected in CADASIL mice compared to controls.
Conclusions:
- Plasma endostatin, HTRA1, and N3ECD, alongside VSMC quantification in retinal arteries, can serve as valuable surrogate endpoints.
- These biomarkers may facilitate the assessment of therapeutic efficacy in preclinical CADASIL studies.
- This research provides a foundation for developing much-needed treatments for 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.
