Neck Vascular Biomechanical Dysfunction Precedes Brain Biochemical Alterations in a Murine Model of Alzheimer's Disease

Age-related vascular changes accompany or precede the development of Alzheimer's disease (AD) pathology. The comorbidity of AD and arterial stiffening suggests that vascular changes have a pathogenic role. Carotid artery mechanics and hemodynamics have been associated with age-related cognitive decline. However, the impact of hemodynamics and vascular mechanics on regional vulnerability within the brain has not been thoroughly explored. Compared with the arterial system, brain venous circulation in cognitive impairment is less understood despite the venous system's role in transport. To study vasculature impact on biochemistry in AD models, we must first establish the differences in vasculature mechanics and hemodynamics in a common AD model compared with healthy controls. With this baseline data, future studies on manipulating vasculature integrity in mice become feasible. Young and aged female 3xTg mice and age-matched controls were imaged using a combination of ultrasound and mass spectrometry. Wall shear stress varied across age and AD models. Mean velocity and pulsatility index varied across age and AD. Liquid chromatography-mass spectrometry of brain tissue revealed several lipids that were statistically different between age and AD, and matrix-assisted laser desorption/ionization MS imaging revealed region-specific differences between groups. Combining both ultrasound and mass spectrometry, we were able to detect significant changes in the vascular biomechanics of neck vasculature prior to observing significant changes in the brain biochemistry. Our work revealed significant vascular differences in the 3xTg compared with controls and, to our knowledge, is the first to study vascular biomechanics via ultrasound in the 3xTg AD mouse model.