Vascular Biomechanics and Brain Biochemistry in Aged and Alzheimer's Disease Mouse Models

Age-related vascular changes accompany or precede the development of Alzheimers disease (AD) pathology. The comorbidity of AD and arterial stiffening may suggest 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 have not been thoroughly explored. Despite the venous systems role in transport, the impact of age-related alterations of the brain venous circulation on cognitive impairment is much less understood compared to the arterial system. By studying vascular mechanics and the resulting spatially-resolved brain lipids in young and aged AD mice, we can determine the relationship between vascular stiffening and brain function. 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 (p<0.05). The circumferential cyclic strain values for the carotid arteries and the WSS values for the jugular veins between groups were measured but were not statistically significant. Both mean velocity and pulsatility index (PI) varied across age and AD (p<0.05). Liquid chromatography mass spectrometry (LC-MS) of brain tissue identified several lipids and metabolites with statistically significant quantities (p<0.05). The fold change was computed for young AD vs. young control, aged AD vs. aged control, aged control vs. young control, and aged AD vs. young AD. The abundance of several lipid headgroups changed significantly with respect to age and AD. Phosphatidylcholines (PC), phosphatidylethanolamines (PE), cardiolipins (CL), phosphatidylserines (PS), and lysophosphatidylcholines (LPC) have been shown to decrease with AD in previous studies. However, we observed a statistically significant increase in PC, PE, CL, PS, and LPC in the aged 3xTG mouse model compared to aged controls. Hexosylceramides (HexCer), ceramides (CER) and sphingomyelin (SM), classes of sphingolipids; lysophosphatidylethanolamine (LPE), a class of phospholipids; and onogalactosyl diglycerides (MGDG), a class of glycerolipids, have been shown to increase with AD in previous studies which aligns with the statistically significant increase of LPC, HexCer, CER, SM, LPE, and MDG observed in the aged 3xTg group compared to controls in this work. Combining both ultrasound imaging and mass spectrometry, we were able determine significant differences in the vascular biomechanics and brain biochemistry seen with aging and AD.