ORCID Profile
0000-0002-6766-4325
Current Organisation
CUMC
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Publisher: Springer Science and Business Media LLC
Date: 07-02-2018
DOI: 10.1038/S41467-018-02926-5
Abstract: With a rapidly aging global human population, finding a cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of understanding of what constitutes the phenotype of aged human microglia—the cell type that has been strongly implicated by genetic studies in the pathogenesis of age-related neurodegenerative disease. Here, we establish the set of genes that is preferentially expressed by microglia in the aged human brain. This HuMi_Aged gene set captures a unique phenotype, which we confirm at the protein level. Furthermore, we find this gene set to be enriched in susceptibility genes for Alzheimer’s disease and multiple sclerosis, to be increased with advancing age, and to be reduced by the protective APOEε2 haplotype . APOEε4 has no effect. These findings confirm the existence of an aging-related microglial phenotype in the aged human brain and its involvement in the pathological processes associated with brain aging.
Publisher: Springer Science and Business Media LLC
Date: 25-05-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-12-2017
DOI: 10.1212/NXI.0000000000000414
Abstract: To study the influence of the Abelson helper integration site 1 ( AHI1 ) locus associated with MS susceptibility on CD4 + T cell function. We characterized the chromatin state of T cells in the MS-associated AHI1 linkage disequilibrium (LD) block. The expression and the role of the AHI1 variant were examined in T cells from genotyped healthy subjects who were recruited from the PhenoGenetic Project, and the function of AHI1 was explored using T cells from Ahi1 knockout mice. Chromatin state analysis reveals that the LD block containing rs4896153, which is robustly associated with MS susceptibility (odds ratio 1.15, p = 1.65 × 10 −13 ), overlaps with strong enhancer regions that are present in human naive and memory CD4 + T cells. Relative to the rs4896153 A protective allele, the rs4896153 T susceptibility allele is associated with decreased AHI1 mRNA expression, specifically in naive CD4 + T cells ( p = 1.73 × 10 −74 , n = 213), and we replicate this effect in an independent set of subjects ( p = 2.5 × 10 −9 , n = 32). Functional studies then showed that the rs4896153 T risk variant and the subsequent decreased AHI1 expression were associated with reduced CD4 + T cell proliferation and a specific differentiation into interferon gamma (IFNγ)–positive T cells when compared with the protective rs4896153 A allele. This T cell phenotype was also observed in murine CD4 + T cells with genetic deletion of Ahi1 . Our findings suggest that the effect of the AHI1 genetic risk for MS is mediated, in part, by enhancing the development of proinflammatory IFNγ + T cells that have previously been implicated in MS and its mouse models.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-12-2017
DOI: 10.1126/SCITRANSLMED.AAI7635
Abstract: A microglial-like cellular model can be used to identify functional consequences of genetic variants associated with neurodegenerative disease.
Publisher: Springer Science and Business Media LLC
Date: 14-01-2021
DOI: 10.1038/S41398-020-01175-9
Abstract: Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer’s disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 540 subjects from two cohort studies of brain aging. Two of these transcriptional programs—modules 113 and 114—relate to the accumulation of β-amyloid, while module 5 relates to tau pathology. We replicate these associations in brain epigenomic data and in two independent datasets. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that three representative module 5 genes ( ACADVL, TRABD , and VASP ) encode proteins that are upregulated in activated microglia in AD.
Publisher: Public Library of Science (PLoS)
Date: 17-08-2020
No related grants have been discovered for Elizabeth Bradshaw.