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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\n                    <jats:sup>ECD<\/jats:sup>\n                    ). The two hallmark features of CADASIL are the loss of arterial smooth muscle cells (SMCs) and the abnormal accumulation of Notch3\n                    <jats:sup>ECD<\/jats:sup>\n                    , without associated accumulation of its transmembrane intracellular domain. Notably, cysteine\u2010altering 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\u2010of\u2010function hypothesis, instead implicating Notch3\n                    <jats:sup>ECD<\/jats:sup>\n                    aggregation, involving both mutant and wild\u2010type NOTCH3, as the primary driver of vascular pathology in CADASIL. Consequently, therapeutic strategies targeting the reduction of Notch3\n                    <jats:sup>ECD<\/jats:sup>\n                    levels in brain arteries, such as antisense therapies, are considered highly promising for clinical development.\n                  <\/jats:p>","DOI":"10.1111\/bcpt.70028","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T03:55:56Z","timestamp":1743306956000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Pathobiology of Cerebrovascular Lesions in CADASIL Small Vessel Disease"],"prefix":"10.1111","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3963-3860","authenticated-orcid":false,"given":"Anne","family":"Joutel","sequence":"first","affiliation":[{"name":"University Paris Cit\u00e9, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266  Paris France"},{"name":"GHU\u2010Paris Psychiatry and 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