Oligodendrocyte stress response as a driver of vascular dementia

Authors

Merour, E., Ghatage, T., Corbett, C., DeBerge, M., Kunjamma, R., Ian Steckler, I. S., Heidari, M., Sorond, F. A., Flanagan, M. E., Thorp, E. B., Popko, B.

Abstract

Vascular dementia (VaD) is a prevalent and devastating neurocognitive disorder characterized by profound white matter damage, yet the precise cellular mechanisms linking cerebrovascular stress to demyelination remain poorly understood. Here, we characterize the impact of a chronic cardiometabolic stress regimen combining a high-fat diet and hypertension (HF/HBP) on central nervous system structure and function. Adult HF/HBP mice exhibit progressive oligodendroglial cell loss and myelin thinning, followed by cognitive impairments, anxiety-like behavior, and memory deficits that recapitulate clinical features of VaD. Mechanistically, we identify the integrated stress response (ISR) as a central driver of this pathology; pharmacological inhibition of the ISR restores myelination, while cell-specific genetic deletion of the ISR-activating kinase PERK from oligodendrocytes fully protects mice from HF/HBP-induced pathological and behavioral defects. Furthermore, we provide translational evidence that the ISR is activated in oligodendrocytes in human cases of cerebrovascular disease. Together, these findings reveal a critical, cell-autonomous role for oligodendroglial ISR activation during cerebrovascular stress and position this pathway as a viable therapeutic target to mitigate VaD pathogenesis.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 14 Oct 2026.

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