O4‐09‐01: Leveraging Mouse Genetic Diversity to Investigate the Role of Brain Myeloid Cells in Alzheimer's Disease
Year: 2019
Type: article
Abstract: Brain myeloid cells have been strongly implicated in Alzheimer's Disease (AD) and related dementias. To understand their role, incorporating genetic diversity into AD models is indispensable to enhance human relevance. The Diversity Outbred (DO) mouse panel has been established by outcrossing incipient inbred Collaborative Cross (CC) strains, derived from eight founder strains including C57BL/6J (B6), PWK/PhJ, WSB/EiJ and CAST/EiJ. These genetically diverse mouse resources provide a promising tool to study the complex etiology of AD. First, 6–8 month male and female mice from four genetically distinct AD models were created (B6, PWK, WSB and CAST each carrying APP/PS1) and assessed by behavioral and metabolic assays. Brain tissue was assessed postmortem by transcriptomics, immunofluorescence and biochemistry. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to identify differential gene modules across the strains. Second, myeloid cells were isolated from 8 month female brains from these four genetically distinct APP/PS1 strains using magnetic activated cell sorting (by CD11b-microbeads) and profiled using single-cell RNA-seq. Third, to begin to understand myeloid cell variation, microglia cell counts and morphology were determined in brains from 120 young DO mice. Finally, myeloid cell responses are being assessed in CC lines carrying APP/PS1 and APOE. Transcriptomics and cell counts showed a significant variation in myeloid cell numbers across B6, PWK, WSB and CAST strains. Also, differential plaque-associated myeloid cell responses were observed in this APP/PS1 panel. Myeloid cell responses correlated with variation in cognitive decline, neurodegeneration, and cerebral amyloid angiopathy across the strains. WGCNA identified myeloid cell-associated gene modules as the greatest difference across the strains with differential expression of Trem2, Tyrobp, Ctss and Csf1r. Protocols for single myeloid cell isolation from genetically distinct strains were established along with a pipeline to determine allelic-specific gene expression. Genetic diversity significantly modifies myeloid cell responses and AD-relevant phenotypes in mice. Mechanistic studies are now underway to understand myeloid cell responses in the founder strains, as well as the DO and CC strains. Projecting the findings to human myeloid cell datasets will facilitate the identification of translatable myeloid-cell based therapies for AD and related dementias.
Source: Alzheimer s & Dementia
Institutions: Jackson Laboratory, Tufts University
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2980654330