The NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation

• DOI: 10.1186/s40478-015-0268-1
• Publication Date: 2015-12-29T13:26:27Z
• Authors: Julie W. Rutten; Roselin R. Klever; Ingrid M. Hegeman; Dana S. Poole; Hans G. Dauwerse; Ludo A. M. Broos; Cor Breukel; Annemieke M. Aart...; J. Sjef Verbeek; Louise van der Weerd; Sjoerd G. van Duinen; Arn M. J. M. van ...; Saskia A. J. Lesn...
• Keywords: CADASIL

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to toxic protein accumulation small- medium sized arterioles. The systemic but most pronounced brain vasculature where it leads clinical symptoms of recurrent stroke dementia. There no therapy for CADASIL, therapeutic development hampered lack feasible outcome measures biomarkers, both mouse models patients. To facilitate pre-clinical interventions we aimed develop novel, translational model. We generated transgenic mice which overexpressed full length human gene from genomic construct archetypal c.544C > T, p.Arg182Cys mutation. four mutant strains have respective RNA expression levels 100, 150, 200 350 % relative endogenous Notch3 expression. Immunohistochemistry on sections shows characteristic vascular all strains, correlating age at onset progression accumulation. This finding was basis developing 'NOTCH3 score', quantitative measure load. score proved be robust sensitive method assess accumulation, biomarker testing. model suitable testing strategies delaying or reversing using as biomarker.