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Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neuritic plaques and intracellular neurofibrillary tangles.Neuritic plaques form in the cerebral cortex and around blood vessels. These plaques contain a dense core of beta-amyloid (Aβ)—a toxic protein fragment that clumps outside neurons. The core is surrounded by damaged neuronal extensions, as well as reactive astrocytes and...
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Related Experiment Video

Updated: Apr 21, 2026

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
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NOTCH3 R545C mutation drives vascular-neuronal dysfunction and cognitive impairment in CADASIL pathogenesis.

Suning Ping1, Bin Hu2, Danni Wu3

  • 1Department of Histology and Embryology, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, Guangdong, China; Neurobiology Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, Guangdong, China.

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|April 19, 2026
PubMed
Summary

Researchers developed a novel mouse model for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). This model mimics East Asian population mutations, revealing cognitive decline and vascular damage, aiding research into this rare genetic disease.

Keywords:
Blood-brain barrier disruptionCADASILCognitive deficitNOTCH3NeuroinflammationSynaptic plasticity

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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.