Abstract WMP114: Changes In Gut Microbiome Precede Cognitive Impairment In A Mouse Model Of Vascular Cognitive Impairment And Dementia

Introduction: Vascular cognitive impairment (VCI) is the second most common cause of clinical dementia after Alzheimer’s disease. VCI results from injury to the cerebral blood vessels. Cerebral perfusion is diminished in elderly individuals and additional reduction of cerebral blood flow increases the risk of developing VCI. These findings have been successfully modeled in mice with bilateral common carotid artery stenosis (BCAS). Age is associated with gut dysbiosis and transplantation of aged microbiome leads to cognitive decline in young animals. However, there are large gaps in our understanding of the molecular mechanisms induced by chronic hypoperfusion contributes to impaired cognitive function. Methods: C57Bl6 aged (~18m) male mice were subjected to a sham or a BCAS surgery using 0.18mm titanium coils placed on both common carotid arteries. Mice were followed for 90d after surgery to assess both gut microbial content and behavioral changes. 16S ribosomal RNA (rRNA) sequencing analysis was performed on fecal samples collected from aged baseline, sham and BCAS animals at 7 and 28 days. Cognition was assessed using Y-maze. Tissues were collected at the time of euthanasia for metabolomics and histological analysis. Results: BCAS resulted in significant reduction of cerebral blood flow, measured using laser speckle (p<0.05; n=4/grp; t test). 16s rRNA analysis revealed BCAS led to a remarkable shift in bacterial diversity as early as day 7 in aged male mice, measured by using unweighted UniFrac analysis. These differences remained significant (p<0.05; n=4/grp) in BCAS compared to sham mice on day 28. In depth analysis revealed significant changes at the genus level between both groups. Interestingly, BCAS mice did not show significant difference in Y-maze at day 14, but significant cognitive impairment was found at day 90 compared to sham mice (n=8-9/grp). Conclusions: We found that chronic cerebral hypoperfusion is associated with significant changes in gut microbiome and cognitive impairment in aged mice. Importantly, shifts in the microbiome preceded cognitive decline. These findings suggest that targeting these detrimental changes in the gut microbiome might be a novel therapeutic strategy to delay or prevent progression of VCI.