CHARACTERIZATION OF A TRANSLATIONAL MOUSE MODEL OF STROKE INTEGRATING ATHEROSCLEROSIS AND CHRONIC NEUROIMMUNE DYSREGULATION

Stroke remains a major cause of mortality and long-term disability, with incidence rising due to increased life expectancy and the growing prevalence of vascular risk factors. Although extensive preclinical research has been conducted, therapeutic advances have been limited, underscoring the need for experimental models that more accurately reflect the clinical complexity of stroke.

To better capture this complexity, we developed a mouse model combining hyperlipidemia-driven atherosclerosis with neuroimmune dysregulation. ApoE⁻/⁻ mice maintained on a high-fat diet were crossed with cortistatin-deficient mice to generate ApoE⁻/⁻:Cort⁻/⁻ animals. Cortistatin is a neuropeptide with recognized immunomodulatory and neuroprotective functions, and its absence has been associated with chronic inflammation and features of accelerated aging. Mice were subjected to middle cerebral artery occlusion and evaluated during acute (2 days) and subacute (7 days) stages after stroke.

At seven days post-ischemia, double knockout animals fed a high-fat diet showed impaired infarct volume recovery, defective glial scar organization, and pronounced blood–brain barrier disruption. To explore molecular mechanisms underlying these outcomes, we performed bulk RNA sequencing of ipsilateral brain tissue two days after ischemia. Transcriptomic profiling revealed widespread gene expression changes indicative of dysregulated immune responses and enhanced activation of neuronal death pathways, effects amplified by both high-fat diet exposure and cortistatin deficiency.

Taken together, these data support the use of ApoE⁻/⁻:Cort⁻/⁻ mice as a clinically relevant platform to dissect interactions between atherosclerosis, neuroimmune dysfunction, and stroke pathology, and to facilitate the identification of novel therapeutic targets.