Potential therapeutic effects of SIRT1 targeting APOE4-induced microvascular endothelial dysfunction

The APOE4 gene markedly increases the risk of Alzheimer's disease (AD),¹ and there is increasing awareness of the effects of APOE4 gene on cognitive impairment. Cerebrovascular dysregulation is an early pathological event before amyloid β deposition and tau phosphorylation during AD development,² and APOE4 carriers are susceptible to amyloid-related imaging abnormalities during anti-amyloid β antibody therapies; therefore, targeting the cerebrovascular system is now considered an important therapeutic strategy among APOE4 carriers. Our experimental studies on young APOE4-targeted replacement (TR) mice revealed that neurovascular function, including endothelial function, is impaired by APOE4 by inducing excessive release of vascular-related reactive oxidative species (ROS) and is rescued by administration of the ROS scavenger MnTBAP.³ Accordingly, impairment of cerebral blood flow and cognitive function is found to be more severe in APOE4-TR mice than in APOE3-TR and wild-type mice under chronic cerebral hypoperfusion.³ In pursuit of a deeper molecular biological understanding, our study identified border-associated macrophages expressing human APOE4, brain-resident myeloid cells in close proximity to cerebral microvessels, as the pathogenic source of excess vascular-related ROS through NADPH oxidase activation.⁴ Weber et al. reported in eBioMedicine that APOE4 was associated with reduction of tight junction proteins, such as ZO-1, in brain microvascular endothelial cells and transendothelial electrical resistance.⁵ Considering that it may be caused by excessive vascular-related ROS, the excessive vascular-related ROS is a promising target to maintain endothelial integrity among APOE4 carriers.

Moreover, Weber et al. reported in eBioMedicine that APOE4-induced microvascular endothelial cell barrier dysfunction is attributed to reduced SIRT1 activity.⁵ This may provide a potential strategy to counteract APOE4-induced microvascular endothelial cell dysfunction, which contributes to cognitive impairment. In a previous study, we demonstrated that SIRT1 improves cerebral blood flow and cognitive impairment in a mouse model of chronic cerebral hypoperfusion to focus on exploring SIRT1's effect on cerebrovascular system.⁶ These benefits were presumed to be due to inhibition of vascular endothelial ROS by SIRT1,⁷ in addition to arteriogenesis induced by endothelial nitric oxide synthase activation.⁶ On further exploration of the impact of SIRT1 in clinical practice, we found that patients with asymptomatic carotid artery stenosis/occlusion who were on long-term resveratrol, a SIRT1 activator, improves cerebral blood flow and cognitive function, including memory and visuospatial/executive function.⁸ To verify the therapeutic effects of SIRT1 or resveratrol on the cerebrovascular system and cognitive function, we are currently conducting a randomised, double-blind, placebo-controlled trial (REsveratrol for VAscular cognitive impairment investigating cerebral Metabolism and Perfusion [REVAMP])⁹ and plan to compare the temporal changes in cerebral blood flow, cognitive function, and amount of ROS between APOE4 noncarriers and APOE4 carriers as an exploratory objective. The administration of resveratrol or SIRT1 activator could be a promising therapeutic option that targets the cerebrovascular system, especially among APOE4 carriers.

Contributors

Conceptualisation and literature search: YH; writing and editing: YH and MI. All authors read and approved the final version of the manuscript, and ensure it is the case.

Declaration of interests

YH received grant support from the Japan Agency for Medical Research and Development (23lk0310090h0001), and Nature Holding Co., Ltd., Osaka, Japan.