<div is a human gene whose product nOTCH4 is a member of the Notch family of transmembrane receptors that mediate cell-cell communication through conserved ligand-receptor interactions. Upon ligand binding (DLL1, DLL4, JAG1, JAG2), Notch4 undergoes proteolytic cleavage, releasing the Notch intracellular domain (NICD) that translocates to the nucleus and regulates gene expression. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration. [1]
NOTCH4 is a member of the Notch family of transmembrane receptors that mediate cell-cell communication through conserved ligand-receptor interactions. Upon ligand binding (DLL1, DLL4, JAG1, JAG2), Notch4 undergoes proteolytic cleavage, releasing the Notch intracellular domain (NICD) that translocates to the nucleus and regulates gene expression.
In the nervous system, NOTCH4 is expressed primarily in endothelial cells and plays important roles in vascular development and blood-brain barrier formation. It is distinct from other Notch receptors in its strong association with the vasculature.
NOTCH4 signaling influences neural stem cell maintenance, astrocyte differentiation, and has been implicated in the neurovascular unit dysfunction observed in neurodegenerative diseases.
Alzheimer's Disease:
CADASIL:
Other Associations:
Expressed predominantly in endothelial cells of brain vasculature. Lower expression in neural stem cells, astrocytes, and certain neuronal populations. NOTCH4 is the least abundant Notch receptor in neurons compared to NOTCH1-3.
γ-secretase inhibitors (notch cleavage blockers) have been trialed but lack specificity. DLL4-neutralizing antibodies in cancer trials. No approved NOTCH4-targeted therapeutics for neurodegeneration.