Asli Uyar, United States of America
The Jackson Laboratory for Genomic Medicine Carter LabAuthor Of 3 Presentations
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.
LIVE DISCUSSION
USING GENETICALLY DIVERSE COLLABORATIVE CROSS MOUSE STRAINS TO MODEL ALZHEIMER’S DISEASE
Abstract
Aims
Mouse models of Alzheimer’s disease (AD), carrying rare variants in genes such as APP and PS1 (APP/PS1), have usually been created on the C57BL/6J (B6J) genetic background. While these strains often exhibit amyloid accumulation and neuroinflammation, many additional molecular alterations present in human AD are absent. To broaden the phenotypes of mouse models, we introduced genetic diversity by incorporating Collaborative Cross (CC) lines, a recombinant inbred mouse panel created from eight highly diverse founder strains.
Methods
Five CC strains were selected for maximal genetic and gene expression variation at twelve late-onset GWAS loci, including TREM2, BIN1, and CLU. Transgenic APPand PS1alleles with a humanized APOE4 allele on a B6J background were crossed with each CC line. Brain hemisphere transcriptomes and neuropathology were assessed at 8-months. Neuropathology focused on amyloid deposition, glial cell activation and neuronal health.
Results
The effect of humanized APOE4 demonstrated differences across CC lines and in the presence of mutant APP and PS1 transgenes. RNA-Seq data revealed allele-specific gene expression profiles associated with neuropathological differences. We mapped strain specific transcriptional signatures to Late-Onset AD subtypes identified in the study cohorts from AMP-AD consortium and observed correlations with subtypes specific to APP/PS1 and APOE4 alleles.
Conclusions
The findings provide new insights into the role of APOE4 in amyloid pathogenesis. Diverse genetic backgrounds of CC lines exhibit a unique resource to assess genome-wide allele-specific gene expression connecting AD risk variants to molecular and neuropathological profiles.This study suggests use of CC lines mouse models to better represent the genetic variation in AD.
Presenter of 2 Presentations
USING GENETICALLY DIVERSE COLLABORATIVE CROSS MOUSE STRAINS TO MODEL ALZHEIMER’S DISEASE
Abstract
Aims
Mouse models of Alzheimer’s disease (AD), carrying rare variants in genes such as APP and PS1 (APP/PS1), have usually been created on the C57BL/6J (B6J) genetic background. While these strains often exhibit amyloid accumulation and neuroinflammation, many additional molecular alterations present in human AD are absent. To broaden the phenotypes of mouse models, we introduced genetic diversity by incorporating Collaborative Cross (CC) lines, a recombinant inbred mouse panel created from eight highly diverse founder strains.
Methods
Five CC strains were selected for maximal genetic and gene expression variation at twelve late-onset GWAS loci, including TREM2, BIN1, and CLU. Transgenic APPand PS1alleles with a humanized APOE4 allele on a B6J background were crossed with each CC line. Brain hemisphere transcriptomes and neuropathology were assessed at 8-months. Neuropathology focused on amyloid deposition, glial cell activation and neuronal health.
Results
The effect of humanized APOE4 demonstrated differences across CC lines and in the presence of mutant APP and PS1 transgenes. RNA-Seq data revealed allele-specific gene expression profiles associated with neuropathological differences. We mapped strain specific transcriptional signatures to Late-Onset AD subtypes identified in the study cohorts from AMP-AD consortium and observed correlations with subtypes specific to APP/PS1 and APOE4 alleles.
Conclusions
The findings provide new insights into the role of APOE4 in amyloid pathogenesis. Diverse genetic backgrounds of CC lines exhibit a unique resource to assess genome-wide allele-specific gene expression connecting AD risk variants to molecular and neuropathological profiles.This study suggests use of CC lines mouse models to better represent the genetic variation in AD.
LIVE DISCUSSION