Hongtian Stanley Yang, United States of America
The Jackson Laboratory ResearchAuthor Of 1 Presentation
WSB/EIJ: A NATURAL GENETIC CONTEXT TO DETERMINE VASCULAR AND NEUROINFLAMMATORY CONTRIBUTIONS TO CEREBRAL AMYLOID ANGIOPATHY IN ALZHEIMER’S DISEASE
Abstract
Aims
Cerebrovascular dysfunction is now considered an early event in many cases of Alzheimer’s disease (AD). Furthermore, microglia-mediated neuroinflammation is implicated as a key driver of disease progression. Previous work in our lab utilizing a panel of wild-derived mouse strains expressing human mutant forms of APP and PS1 determined inclusion of genetic diversity provides greater human relevance to model AD complexity. One strain, WSB.APP/PS1, exhibited lower numbers of parenchymal amyloid plaques, but significant vascular associated plaque via cerebral amyloid angiopathy (CAA), partnered with robust fibrin leakage.
Methods
Bulk brain and single-cell microglia RNA-sequencing was performed on our wild-derived AD mouse panel at 8 months. Differences in vascular integrity and microglia subtypes were validated using immunofluorescence at multiple ages.
Results
Transcriptional profiling of bulk brain tissue revealed WSB.APP/PS1-specific enrichment of genes relating to vascular health including basement membrane (Col4a2, Col6a4, Mmp2), endothelial function (Ednra), and blood vessel formation (Vegfr and Pdgfr8). Single-cell RNAseq uncovered differences in the proportion and expression profiles of previously identified microglia subclusters. Unlike other strains, WSB.APP/PS1 did not demonstrate significant increases in disease-associated or interferon-responding microglia compared to wild type (WT) counterparts. Interestingly, a population of homeostatic microglia enriched for expression of P2ry12 was only present in WSB but not WSB.APP/PS1 or other WT or AD strains. P2RY12-mediated chemotaxis is critical for closure of the blood brain barrier after injury.
Conclusions
These data suggest the WSB genetic background is ideal to dissect the role of vascular dysfunction and neuroinflammation in CAA in AD and neurodegenerative diseases.