Abstract WP136: Peripheral Activation of Gut-Immune-Brain Axis in Cerebral Amyloid Angiopathy

Abstract

Cerebral Amyloid Angiopathy (CAA) is an emerging cause of vascular cognitive impairment in the elderly. CAA is characterized by amyloid-β (Aβ) deposition in the central nervous system (CNS) vasculature and is associated with increased neuroinflammation. Aging is risk factor for CAA and is accompanied by low-grade inflammation and gut dysbiosis (a pathological imbalance of microbial organisms in the gut). Activation of peripheral immunity by a dysfunctional gut-immune axis may contribute to CAA progression. We hypothesize that CAA-induced gut dysbiosis leads to activation of a peripheral immune response which can accelerate CAA progression. We used the Tg-SwDI mouse (harboring Swedish, Dutch, and Iowa mutations of human amyloid precursor protein (APP), “CAA mice”) model that develops cerebral Aβ deposits and cognitive deficits around 3-4 months. We used 2mo mice as pre-onset and 10mo mice as post-onset groups. Results: Our preliminary fecal 16S rRNA sequencing data showed higher microbiome alpha- (or “within-sample”) diversity in CAA mice (n=207, Inverse-Simpson diversity score, p=0.036). Upon visualization of beta- (or “between samples”) diversity in CAA and WT animals, with weighted-UniFrac-distances by principal coordinate analysis (PCoA), we found a notable clustering by strain (34.6% and 26.4% PCoA axes, p=0.001). Immunophenotyping of liver showed significant decrease in the B:T cell ratios when comparing the pre- to post-onset CAA mice (0.53 vs. 0.19, p = 0.005). Additionally, we observed a significant increase in the relative frequency of MHC-II (high) non-myeloid cells, when comparing the pre- to post-onset CAA (11.5% vs. 41.8%, p = 0.027). Conclusion: Our findings suggest that gut dysbiosis occur early in CAA pathogenesis and may be responsible for ongoing increased peripheral and CNS inflammation. This work is significant if follow-up studies confirm that manipulation of the gut microbiota can modulate the peripheral immune response to reduce neuroinflammation in CAA and improve CAA-associated cognitive phenotype.