Large artery stiffness and brain health: insights from animal models

There are no effective treatments available to halt or reverse the progression of age-related cognitive decline and Alzheimer's disease. Thus, there is an urgent need to understand the underlying mechanisms of disease etiology and progression to identify novel therapeutic targets. Age-related changes to the vasculature, particularly increases in stiffness of the large elastic arteries, are now recognized as important contributors to brain aging. There is a growing body of evidence for an association between greater large artery stiffness and cognitive impairment among both healthy older adults and patients with Alzheimer's disease. However, studies in humans are limited to only correlative evidence, whereas animal models allow researchers to explore the causative mechanisms linking arterial stiffness to neurocognitive dysfunction and disease. Recently, several rodent models of direct modulation of large artery stiffness and the consequent effects on the brain have been reported. Common outcomes among these models have emerged, including evidence that greater large artery stiffness causes cerebrovascular dysfunction associated with increased oxidative stress and inflammatory signaling. The purpose of this mini-review is to highlight the recent findings associating large artery stiffness with deleterious brain outcomes, with a specific focus on causative evidence obtained from animal models. We will also discuss the gaps in knowledge that remain in our understanding of how large artery stiffness affects brain function and disease outcomes.