Oligodendrocyte stress response as a driver of vascular dementia

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.