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CADASIL: experimental insights from animal models
1Neurovascular Research Laboratory, Department of Radiology, and Stroke Service and Neuroscience Intensive Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Mass 02129, USA. cayata@partners.org
Insights
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetic small vessel disease. Animal models help investigate NOTCH3 gene mutations and CADASIL mechanisms.
Area of Science:
- Neurology
- Genetics
- Vascular Biology
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common monogenic inherited small vessel disease.
- It presents with migraines, strokes, and progressive white matter degeneration, leading to subcortical dementia.
- Pathology involves NOTCH3 gene mutations, granular osmiophilic material accumulation, and vascular smooth muscle cell loss.
Purpose of the Study:
- To provide an overview of existing animal models for CADASIL.
- To explore pathophysiological insights gained from these models.
- To investigate the role of NOTCH3 gene mutations in CADASIL.
Main Methods:
- Review of existing literature on CADASIL animal models.
- Analysis of pathological and physiological data from experimental models.
- Comparison of findings across different species and genetic constructs.
Main Results:
- Animal models replicate CADASIL pathology and cerebrovascular dysfunction.
- Phenotypic heterogeneity observed in models, potentially due to genetic constructs and species differences.
- Models offer opportunities to study molecular and physiological mechanisms of CADASIL.
Conclusions:
- Animal models are valuable tools for understanding CADASIL.
- Further research is needed to elucidate whether the CADASIL phenotype results from loss or gain of NOTCH3 function.
- These models can guide the development of targeted therapies for CADASIL.
Abstract:
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) syndrome is the most common monogenic inherited form of small vessel disease, characterized by frequent migraine attacks with aura, recurrent strokes and progressive white matter degeneration. Early vascular cognitive impairment progresses into frank dementia of subcortical type later in life. Linked to mutations in the NOTCH3 gene, CADASIL vasculopathy is associated with accumulation of granular osmiophilic material and NOTCH3 extracellular domain around small caliber arteries and arterioles, and eventual loss of vascular smooth muscle cells. Cerebral blood flow dysregulation has been hypothesized as a major mechanism, largely based on evidence from hemodynamic studies in CADASIL patients. Although animal models expressing CADASIL mutations reproduced the pathology and cerebrovascular dysfunction, the phenotypic spectrum has been quite heterogeneous, possibly due to the choice of genetic constructs and obvious species differences between mouse and man. Nevertheless, these experimental models provide new opportunities to explore the molecular and physiological mechanisms of CADASIL, and address the fundamental question of whether CADASIL phenotype represents loss of NOTCH3 function or gain of a novel and pathological function. Here, I provide an overview of existing animal models of CADASIL and the pathophysiological insights gained from these models.