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Role of interstitial fluid drainage in aggregate clearance failure in CADASIL

Determine whether impaired interstitial fluid (ISF) drainage contributes to failure of clearance of NOTCH3 ectodomain aggregates in CADASIL.

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Background

CADASIL and Alzheimer’s disease are categorized as protein elimination failure angiopathies, where impaired clearance of extracellular protein aggregates is hypothesized to contribute to pathology. Whether interstitial fluid drainage mechanisms specifically affect removal of NOTCH3 ectodomain aggregates in CADASIL is uncertain.

Clarifying this would inform strategies for immunotherapy and other aggregate-targeting interventions by identifying whether enhancing ISF drainage could improve aggregate clearance.

References

Several reviews have claimed that CADASIL symptoms may be exacerbated by a lack of drainage of the protein aggregates, although it is unclear if a lack of interstitial fluid (ISF) drainage is actually a factor in the removal of protein aggregates in CADASIL [47-49].

— Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL): Immunotherapy and Cell Therapy approaches (2506.09293 - Haile et al., 10 Jun 2025) in Immunotherapy in CADASIL