Endothelial TRIM47 regulates blood-brain barrier integrity and cognition via the KEAP1/NRF2 signalling pathway in mice

TL;DR

This study shows that TRIM47 in brain blood vessels helps protect the brain from damage and cognitive decline by controlling oxidative stress through the KEAP1/NRF2 pathway.

Contribution

The study reveals a novel role of endothelial TRIM47 in regulating BBB integrity and cognition via the KEAP1/NRF2 pathway in mice.

Findings

Trim47-deficient mice show cognitive impairments and increased BBB permeability.

TRIM47 stabilizes NRF2 protein levels by binding to KEAP1, reducing oxidative stress in brain endothelial cells.

Activating NRF2 prevents BBB and cognitive defects in Trim47-mutant mice.

Abstract

Cerebral small vessel disease (cSVD) is a leading cause of stroke, cognitive decline and dementia, for which no specific mechanism-based treatments are currently available. Previous genomic studies identified associations of common variants at chr17q25 with cSVD features, with converging evidence for a causal involvement of TRIM47, an ubiquitin ligase enriched in brain endothelial cells (ECs). In the present study, we devised a multilayered experimental plan to decipher the biological mechanisms underlying TRIM47’s role in cSVD pathophysiology. Trim47-deficient mice, which model the human genetic anomaly, exhibit major cognitive impairments, increased blood-brain barrier (BBB) permeability, and astrogliosis, without neuroinflammation. Inducible deletion of Trim47 in ECs recapitulates these phenotypes highlighting the contribution of endothelial TRIM47 in maintaining brain homeostasis. In vitro and in vivo data, demonstrate that TRIM47 regulates the resilience of brain ECs to oxidative stress by binding to KEAP1, stabilizing NRF2 protein levels and promoting the NRF2 pathway. Treatment with the NRF2 activator tert-butylhydroquinone prevented BBB and cognitive impairment in Trim47-mutant mice. By leveraging unique human proteomic data, we propose that modulation of the TRIM47/NRF2 pathway could predict an increased susceptibility to cSVD, suggesting that targeting this pathway may offer a promising therapeutic approach for vascular cognitive impairment and dementia.

Functional analysis of TRIM47 uncovers its role in regulating endothelial oxidative stress responses and Blood-Brain-Barrier stability in the mouse, linking KEAP1/NRF2 pathway dysregulation to cognitive decline in vascular dementia.

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