We have studied the relationship of Notch receptor processing and two diseases of the central nervous system: Alzheimer's disease (AD) and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). The Notch receptor signalling pathway plays a crucial role during development in many different species for directing adjacent cells to adopt different fates. During maturation and ligand activation the Notch receptor undergoes a series of complex proteolytic cleavages before the intracellular domain is released and translocated to the nucleus where it affects transcription. The first cleavage (S 1) occurs during the transport out to the plasma membrane in the trans-Golgi compartment by a furin-like convertase. This cleavage is constitutive and generates a bipartite receptor, where the two Notch fragments are held together through non-covalent forces. The second cleavage (S2) occurs near the transmembrane region at the extracellular side when Notch is ligand- activated. The S2 cleavage is immediately followed by the third cleavage (S3) at the border of the transmembrane region and the intracellular side. The metalloprotease TACE (TNFalpha converting enzyme) has been shown to be responsible for the S2 cleavage, while the S3 cleavage is dependent on presenilins (PSs). The PSs have been genetically linked to familial AD and are involved in the gamma-secretase cleavage of the betaamyloid precursor protein (APP) and the production of the neurotoxic Abeta peptide, which causes senile plaques in the brain. There are four known mammalian Notch receptors (Notch 1-Notch 4) with overlapping patterns of expression, but the role of the different Notch receptors is not that well understood. Mutations in the Notch 3 gene cause the genetic disorder CADASIL. CADASIL is an inherited form of stroke and dementia and the histopathological hallmarks are degeneration of vascular smooth muscle cells and deposits of granular osmiophilic material between the vascular smooth muscle cells. The mutations ...