Vascular cognitive impairment (VCI) is a common form of dementia associated with cerebrovascular dysfunction and chronic inflammation. Impaired cerebral perfusion is a result of atherosclerotic plaque build-up in the medium and large arteries in the brain and is exacerbated by numerous inflammatory triggers, including aging, high blood pressure, high cholesterol, and smoking. Previously, we demonstrated that receptor-interacting protein 1 kinase (RIPK1) promotes the progression of aortic atherosclerosis and NFκB activation in mice, and that atherosclerotic vascular disease was decreased by therapeutically inhibiting RIPK1 with antisense oligonucleotides. Given the relationship between atherosclerosis and cognitive impairment, we hypothesize that RIPK1 also contributes to the development of cerebrovascular disease and neuroinflammation in a mouse model of hyperlipidemia. Male and female Apoe −/− were fed a chow or Western diet (WD) for 16 weeks and subsequently treated for an additional 8 weeks with either scramble (control) or anti-RIPK1 antisense oligonucleotides (ASO) to systemically knockdown RIPK1 expression (RIPK1 KD ). WD feeding induced significant carotid atherosclerotic lesion burden and reduced cerebral blood flow compared to chow-fed mice. These vascular changes were associated with impaired spatial learning and memory, reduced hippocampal vascularity, and altered expression of neurovascular and inflammatory markers. Systemic RIPK1 silencing significantly reduced carotid artery lesion size, restored arterial stiffness and blood flow in the brain. Furthermore, treatment with RIPK1 KD preserved vascularity in the hippocampus, restored blood flow in the brain and prevented the impairment in spatial learning and memory. Overall, our study identifies RIPK1 as a mediator of hyperlipidemia-induced cerebrovascular dysfunction and suggests that targeting RIPK1 may represent a therapeutic approach to limit cognitive impairment.
Salazar‐León et al. (Fri,) studied this question.