Investigating the impact of Apolipoprotein isoforms on cerebral blood flow and behavioural differences in mice in response to bilateral carotid artery stenosis surgery

Abstract

BACKGROUND: Research has shown cognitive impairment to be associated with ageing, specifically in regard to Alzheimer’s disease and vascular cognitive impairment. In mouse models of vascular cognitive impairment, it has been shown that chronic cerebral hypoperfusion causes white matter damage, which increases the microglial population and causes functional impairment in white matter tracts. As shown by human longitudinal cohort studies and genome-wide association studies, Apolipoprotein E4 (ApoE4) is a prominent genetic risk factor for Alzheimer’s disease and related cognitive impairment. We are interested in investigating the impact of APOE genotype on cerebral blood flow and behavioural differences in mice in a mouse model of vascular cognitive impairment.

METHODS: Using genetically modified mice models with transgenic human APOE isoforms, we induced cerebral hypoperfusion using bilateral carotid artery stenosis surgery to mimic vascular cognitive impairment. This was done using 2 x 0.18mm microcoils on the common carotid arteries. Cerebral blood flow changes were measured using laser speckle contrast imaging at baseline, 24 hour, 1 week, and 8 weeks postsurgery. This was done to ensure mice were hypoperfused after surgery. Mice with less than 30% cortical blood flow reduction at both 24 hours and 1 week post-surgery were excluded from the study due to lack of significant hypoperfusion. In order to test cognitive ability, five behavioural tests were selected. This includes spontaneous alternation and forced alternation (1 minute inter-trial interval and 2 hour inter-trial interval) done using a Y-maze, and novel object recognition and novel object in place, done using an open field. Spontaneous alternation measures spatial working memory and acts as a baseline for the natural curiosity of the rodent. The forced alternation test measures spatial reference memory, but the 1 minute ITI tests short-term spatial reference memory, whereas 2 hour ITI tests long-term spatial reference memory. Novel object recognition measures non-spatial declarative episodic memory, whereas novel object in place measures spatial declarative episodic memory.

RESULTS: After exclusion and inclusion criterions were applied to the mice, we see that there is no significant impact of APOE genotype on baseline cerebral blood flow, cerebral blood flow post-surgery, spatial working memory, short-term and long-term spatial reference memory, non-spatial declarative episodic memory, and spatial declarative episodic memory. In conclusion, the results from our study are opposite to the results from human longitudinal cohort studies and genome-wide association studies of vascular cognitive impairment.