Investigating cerebrovascular function in pre-clinical models of health and disease

Background: Alzheimer’s disease (AD) is the leading cause of dementia. Over 50 million people are currently living with dementia world-wide, and this is set to increase to over one hundred and thirty-nine million by 2030. However, AD is not a disease that occurs in isolation, with many people experiencing comorbidities, a number of which impact the vasculature, such as atherosclerosis. Yet, studies investigating AD often do not explore the impact of comorbidities on disease pathology. Therefore, I wanted to explore how comorbid disease, namely atherosclerosis, may impact cognitive and vascular function. One study has previously investigated the impact of atherosclerosis on AD. However, they used a mild model of AD and completed the neurovascular assessment under lightly anaesthetised conditions. Therefore, part of my work aimed to extend and replicate this study, by using a more ‘severe’ model of AD and completing vascular assessments in awake conditions.

Aims: As this research is conducted in awake mice, I firstly needed to investigate the effect of locomotion on sensory-evoked haemodynamic responses (chapter 2). My second aim was to investigate cognition in the APP/PS1 mouse model of AD, a model of atherosclerosis, and a mixed model of AD and atherosclerosis (chapter 3). My third aim was to investigate neurovascular function (using 2D-OIS) in the APP/PS1 mouse model of AD, a model of atherosclerosis and a mixed model of AD and atherosclerosis (chapter 3). My fourth aim was to investigate the effect of mixed disease on amyloid pathology (chapter 3). As a result of observations within my initial studies, my fifth aim was to explore the novel phenomenon relating to locomotion and early vascular responses in large draining veins of the brain (chapter 4).

Results: I found that the timing of locomotion can significantly impact sensory-evoked haemodynamic responses. This was especially relevant when locomotion occurred prior to or during whisker stimulation. I observed preserved recognition memory in AD, atherosclerosis and mixed disease mice. I observed preserved vascular responses in the APP/PS1 AD mouse model and mixed AD and atherosclerosis model. I found no impact of disease on vascular function when locomotion was ignored. However, I did observe deficits in the evoked-haemodynamic response in the atherosclerosis group, during the least locomotion trials, when locomotion was ranked during the whisker stimulation. I also found no evidence of increased amyloid pathology in mixed disease mice. Finally, in studies where I assessed vascular responses to spontaneous locomotion, I observed a previously unreported phenomena, whereby the onset of locomotion appeared to cause a large and fast decrease in cerebral blood volume (CBV) within large draining veins.

Conclusions: This work suggests that locomotion should be monitored during awake haemodynamic imaging experiments, as it can significantly impact sensory-evoked haemodynamic responses. Additionally, the work extended and replicated previous findings regarding the presence of vascular dysfunction in an atherosclerosis model. The work further adds to the literature regarding the observation of no vascular deficits in an AD and mixed disease model. Finally, the work suggests that large draining veins of the brain may be important regulators of CBV during locomotion.