NOTCH3 R545C mutation drives vascular-neuronal dysfunction and cognitive impairment in CADASIL pathogenesis

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary small vessel disease.
• Pathogenic mechanisms of CADASIL, particularly the common NOTCH3 p.Arg544Cys mutation in East Asians, are not fully understood.

Purpose of the Study:

• To develop a novel CRISPR/Cas9-mediated mouse model for CADASIL.
• To investigate the pathogenesis of CADASIL using a mouse model with the NOTCH3 p.R545C mutation, orthologous to the human R544C mutation.

Main Methods:

• CRISPR/Cas9 gene editing to create a NOTCH3 p.R545C point mutation mouse model.
• Comprehensive phenotyping including cognitive tests, synaptic plasticity assessment, and detailed neuropathological analysis.
• RNA sequencing of hippocampal tissues to identify molecular pathways involved in CADASIL.

Main Results:

• The mouse model exhibited age-dependent cognitive deficits, impaired spatial learning, and memory.
• Pathological findings included blood-brain barrier disruption, granular osmiophilic material deposition, and cerebrovascular degeneration.
• RNA sequencing revealed dysregulated genes in neuroendocrine signaling, cytoskeletal organization, and inflammatory pathways.

Conclusions:

• The NOTCH3 p.R545C mouse model effectively recapitulates key features of CADASIL prevalent in East Asian populations.
• The study suggests a vascular-initiated neural damage mechanism in CADASIL progression.
• The model provides a valuable platform for mechanistic studies and identifying therapeutic targets for CADASIL.