The Pathobiology of Cerebrovascular Lesions in CADASIL Small Vessel Disease

Abstract

Cerebral small vessel disease (cSVD) is a significant global health issue, accounting for approximately 25% of ischemic strokes and 20% of all dementia cases. CADASIL, the most common monogenic form of cSVD, is caused by stereotyped mutations in the NOTCH3 receptor that alter the number of cysteine residues in its extracellular domain (Notch3^ECD). The two hallmark features of CADASIL are the loss of arterial smooth muscle cells (SMCs) and the abnormal accumulation of Notch3^ECD, without associated accumulation of its transmembrane intracellular domain. Notably, cysteine-altering mutations in NOTCH3 are prevalent in the general population, and although they are not directly associated with classical CADASIL disease, they are still linked to an elevated risk of stroke and dementia. NOTCH3 is predominantly expressed in the mural cells of small blood vessels and plays an essential role in the development, maintenance, function and survival of arterial SMCs. Recent research has challenged the loss-of-function hypothesis, instead implicating Notch3^ECD aggregation, involving both mutant and wild-type NOTCH3, as the primary driver of vascular pathology in CADASIL. Consequently, therapeutic strategies targeting the reduction of Notch3^ECD levels in brain arteries, such as antisense therapies, are considered highly promising for clinical development.