Tiny Fish 'Zebrafish' Hold the Key to Unraveling Rare Disease! - Successful Recreation of Juvenile Dementia 'CADASIL'

A research group led by Wgo Kano (then a fourth-year doctoral student at Chiba University Graduate School of Medicine and Pharmaceutical Sciences) and Professor Motoyuki Itoh from the Graduate School of Pharmaceutical Sciences, along with Group Director Yoshinori Hasegawa and Deputy Director Osamu Ohara from the Kazusa DNA Research Institute, in collaboration with the Chiba University Center for Medical Mycology and the National Institutes for Quantum Science and Technology, has pioneered the establishment of a novel disease model for the hereditary cerebrovascular disease 'CADASIL' (Note 2) using zebrafish (Note 1). Analysis using this model revealed that the functional decline of 'Type IV Collagen' (Note 3) around cerebral blood vessels is involved in disease progression. This discovery is expected to lead to the identification of new therapeutic targets for this disease, for which no fundamental treatment has existed until now. This research achievement was published on June 3, 2026, in the academic journal Acta Neuropathologica Communications. (Paper here: 10.1186/s40478-026-02333-8)

Figure: Overview of this research

Background of the Research

CADASIL is a serious disease that damages the small blood vessels in the brain, causing strokes and dementia from a young age. The cause is an abnormality in the NOTCH3 (Note 4) gene, and various mutations are known, leading to different symptoms. Previously, conventional mouse models have faced challenges in adequately replicating the memory impairment and brain atrophy observed in humans. Therefore, this research group focused on zebrafish, which have vascular structures and aging processes similar to humans, aiming to reproduce the pathology and elucidate the progression mechanism.

Key Research Findings

① Recreation of Human Pathology: In the zebrafish CADASIL model established in this study, a disease course common to human patients was observed, including reduced cerebral blood flow and decreased memory capacity with aging.

② Discovery of 'Collagen' Reduction: Latest analysis revealed a decrease in 'Type IV Collagen,' which supports blood vessels, and related substances in the brains of diseased zebrafish (Figure).

③ Impact of 'Specific Amino Acid Mutation': Structural analysis using AI (AlphaFold3) indicated that this mutation shares common characteristics with patients prone to cerebral hemorrhage and is a type prevalent in East Asia, including Japan.

Future Prospects (Researcher Comments)

This research provides new insights into the relationship between CADASIL-causing gene mutations and Type IV Collagen, and the identification of new therapeutic targets is anticipated. Furthermore, this study demonstrates that zebrafish are a useful model that can complement mouse models and reproduce human pathology. It is expected that further elucidation of CADASIL's pathogenesis will be achieved through the creation and analysis of models with diverse NOTCH3 mutations.

Glossary

Note 1) Zebrafish: A small freshwater fish belonging to the bony fish class, native to India. It is widely used in research due to its ease of breeding, prolificacy, and rapid development. While historically used as a model for studying individual development using embryos, it has recently gained attention as a model for studying aging.

Note 2) CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy): English abbreviation for Intractable Disease No. 124 designated by the Ministry of Health, Labour and Welfare. It is a condition where repeated strokes (cerebral infarction and cerebral hemorrhage) due to damage to small cerebral blood vessels lead to dementia. Typically, it is caused by the replacement of a single amino acid residue in the NOTCH3 protein with another amino acid, and over 200 types of 'NOTCH3 gene mutations' are reported to cause CADASIL.

Note 3) Type IV Collagen: A major component of the 'basement membrane' that exists between cells and tissues, supporting cells. Around blood vessels, it forms a mesh-like structure, playing a role in maintaining vascular strength and flexibility.

Note 4) NOTCH3: A type of receptor protein Notch present in the cell membrane, composed of extracellular and intracellular domains. It is highly expressed in cells surrounding blood vessels and plays a role in promoting cell proliferation and survival.

Publication Information

Title: Age-Dependent Vascular and Neurological Characteristics of CADASIL Are Recapitulated in Notch3 Mutant Zebrafish, Implicating a Role for Type IV Collagen in Disease Progression

Authors: Tohgo Kanoh, Shiho Oubayashi, Kengo Furukawa, Kosuke Fujimoto, Amane Inoue, Takamasa Mizoguchi, Masashi Yamaguchi, Azusa Takahashi-Nakaguchi, Yoshinori Hasegawa, Osamu Ohara, Ichio Aoki, Motoyuki Itoh

Journal: Acta Neuropathologica Communications

DOI: 10.1186/s40478-026-02333-8

About the Research Project

This research was supported by the following grants:

- Japan Society for the Promotion of Science (JSPS): Grants-in-Aid for Scientific Research (B) (JP18H02568, JP21H02621), Grants-in-Aid for Scientific Research (C) (JP25K09486), Research Fellowships for Young Scientists (JP25KJ0721), J-PEAKS (JPJS00420230002)

- Japan Science and Technology Agency (JST): Project for nurturing core researchers on fusion and solidarity of all fields (JPMJSP2109) Program for Leading Graduate Schools of Innovative Medical Science CHIBA