Hippocampal Perfusion in a Mouse Model of Greater Large Artery Stiffness and Alzheimer’s Disease‐Related Transgenes

Abstract

Numerous recent studies have identified correlations between greater large artery stiffness and cognitive impairment and/or Alzheimer’s disease (AD). However, the mechanisms behind these relations are currently unknown. AD‐related pathology is characterized by an accumulation of amyloid‐β and tau protein aggregates. Greater large artery stiffness, amyloid‐β, and tau pathology are all independently associated with impaired cerebrovascular function. These cerebrovascular impairments may lead to a reduced cerebral perfusion, a potential cause of cognitive impairment. Thus, we hypothesized that greater large artery stiffness and AD‐related pathology would interact to impair cerebral perfusion.In order to examine the effects of elevated large artery stiffness, we studied the elastin haploinsufficient (Eln+/−) mouse. We previously established that Eln+/− mice have greater aortic stiffness when compared with Eln+/+ mice, similar to the increases in large artery stiffness that occur with aging. To understand the potential interaction of large artery stiffness and AD‐related pathology, we crossed Eln+/− mice with the 3xTg‐AD mouse model (mutant transgenes for amyloid precursor protein, presenilin‐1, and tau). The groups consisted of male and female mice at 14–16 months of age with the following genotypes: Eln+/+ (n=13), Eln+/− (n=13), Eln+/+ x 3xTg‐AD (n=5), and Eln+/− x 3xTg‐AD (n=8). Cerebral perfusion was obtained in anesthetized mice by arterial spin labeling MRI under both normoxic and hypercapnic (5% CO2) conditions. Perfusion through the hippocampus was analyzed using JIM image analysis software (Xinapse Systems). Among non‐3xTg‐AD mice, Eln+/− mice had a 20% lower hippocampal perfusion compared with Eln+/+ mice during normoxia (p=0.04). In response to hypercapnia, hippocampal perfusion increased by 34±8% in Eln+/− mice, which was greater than the increased perfusion of 16±5% in Eln+/+ mice (p=0.03). Among 3xTg‐AD mice, there was no difference in hippocampal perfusion during normoxia for Eln+/− x 3xTg‐AD vs. Eln+/+ x 3xTg‐AD mice (p=0.34). In contrast, in response to hypercapnia Eln+/− x 3xTg‐AD mice had only a 5±8% increase in hippocampal perfusion compared with a 21±4% increase in perfusion in Eln+/+ x 3xTg‐AD mice (p=0.05). There was an interaction between Eln and 3xTg‐AD genotype for the increase in hippocampal perfusion with hypercapnia (p=0.03), but no interaction for hippocampal perfusion during normoxia (p=0.18).In conclusion, these results suggest large artery stiffness leads to a decline in hippocampal perfusion under normoxia, but augments the hippocampal perfusion response to hypercapnia. The presence of AD‐related pathology may negate the effects of large artery stiffness on hippocampal perfusion under normoxic conditions. The combination of greater large artery stiffness and AD‐related pathology lead to a reduced hippocampal perfusion response to hypercapnia.Support or Funding InformationFunded by the Oregon Alzheimer’s Tax Checkoff Fund