Drugs Modulating CD4+ T Cells Blood-Brain Barrier Interaction in Alzheimer's Disease

Kubick, Norwin; Flournoy, Patrick C. Henckell; Enciu, Ana‐Maria; Mickael, Michel‐Edwar; Manda, Gina

doi:10.20944/preprints202008.0500.v1

Cited by 12 publications

(5 citation statements)

References 84 publications

(117 reference statements)

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“…CD4+ effector cells can produce autoantibodies against amyloid and therefore harbour protection against amyloid burden. 68 It is thought that genetic drivers of immune-cell profiles may in part explain sex differences observed in response to Alzheimer’s disease pathology. 69 , 70 Thus, it is noteworthy to see an immune-target arise at both the variant-level with GATA3 , and at the whole genome level with our genetic correlation analyses.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the genetic architecture of cognitive resilience to Alzheimer’s disease

Eissman

Dumitrescu

Mahoney

et al. 2022

Brain

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Approximately 30% of elderly adults are cognitively unimpaired at time of death despite presence of Alzheimer’s disease (AD) neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of AD neuropathology may uncover novel therapeutic targets to treat AD. It is well-established that there are sex differences in response to AD pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large-scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive aging, in-vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified (N(males) = 2,093, N(females) = 2,931) and sex-interaction (N(both sexes) = 5,024) genome-wide association studies (GWAS), gene- and pathway-based tests, and genetic correlation analyses to clarify the variants, genes, and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 (rs827389, β(females) = 0.08, P(females) = 5.76E-09, β(males)=-0.01, P(males) = 0.70, β(interaction) = 0.09, P(interaction) = 1.01E-04) in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus, and highlighted numerous sex-specific molecular pathways that may underly resilience to AD pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with AD may be personalized based on their biological sex and genetic context.

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Section: Discussionmentioning

confidence: 99%

Sex differences in the genetic architecture of cognitive resilience to Alzheimer’s disease

Eissman

Dumitrescu

Mahoney

et al. 2022

Brain

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“…Multiple studies in neurological diseases such as Alzheimer's disease and multiple sclerosis suggested that T lymphocytes were closely related to BBB destruction (28,29). Before entering the brain parenchyma, pro-inflammatory CD17+ T cells were interacted closely with vascular endothelial cells by promoting the downregulation of tight junction protein and adhesion protein, stimulating the expression of pro-inflammatory cytokines, and promoting the transmigration of CD4+ T cells (27,28). The infiltrated CD8+ T cells also showed to be involved in BBB destruction through a perforin-dependent process (30).…”

Section: Discussionmentioning

confidence: 99%

Identification of mRNA expression biomarkers associated with epilepsy and response to valproate with co-expression analysis

Min

Chen²,

Wu³

et al. 2022

Front. Neurol.

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PurposeValproate (VPA) resistance was reported to be an important predictor of intractable epilepsy. We conducted this study to identify candidate biomarkers in peripheral blood correlated with VPA resistance.MethodsThe microarray dataset (GSE143272) was downloaded from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was performed to construct co-expression modules and obtain the most prominent module associated with VPA resistance. Differentially expressed genes (DEGs) between VPA-responsive and VPA-resistant patients were obtained using the “Limma” package in R. The intersections between the most prominent module and DEGs were identified as target genes. Metascape was performed to discover the possible involved pathways of the target genes. GeneCards database was used to know the function of each target gene.ResultsAll genes in the GSE143272 were divided into 24 different modules. Among these modules, the darkred module showed a pivotal correlation with VPA resistance. A total of 70 DEGs between VPA-responsive and VPA-resistant patients were identified. After taking the intersection, 25 target genes were obtained. The 25 target genes were significantly enriched in T cell receptor recognition, T cell receptor signaling pathway, regulation of T cell activation, cytokine–cytokine receptor interaction, and in utero embryonic development. Half of the target genes (CD3D, CD3G, CXCR3, CXCR6, GATA3, GZMK, IL7R, LIME1, SIRPG, THEMIS, TRAT1, and ZNF683) were directly involved in the T cell development, migration, and activation signaling pathway.ConclusionWe identified 25 target genes prominently associated with VPA resistance, which could be potential candidate biomarkers for epilepsy resistance in peripheral blood. The peripheral blood T cells may play a crucial role in VPA resistance. Those genes and pathways might become therapeutic targets with clinical usefulness in the future.

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“…An interesting topic also is the detection of different isoforms and alternative splicing cases of microglial markers 71 . The effect of drugs on the Interaction between microglia and CD4+ T cells infiltrating the brain during neurodegenerative diseases is another one 72 . These developments could support scRNA‐seq becoming a plausible alternative to classical cellular clustering methods.…”

Section: Discussionmentioning

confidence: 99%

What has single‐cell RNA sequencing revealed about microglial neuroimmunology?

Kubick

Flournoy²,

Klimovich³

et al. 2020

Immunity Inflam & Disease

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The use of single‐cell RNA sequencing (scRNA‐seq) in microglial research is increasing rapidly. The basic workflow of this approach consists of isolating single cells, followed by sequencing. scRNA‐seq is capable of examining microglial heterogeneity on a cellular level. However, the results gained from applying this technique suffer from discrepancies due to differences between applied methods characteristics such as the number of cells sequenced and the depth of sequencing. This review aims to shed more light on the recent developments that happened in this field and how they are related to the methods used. To do that, we track the progress and limitations of various scRNA‐seq methods currently available. The review then summarizes the current knowledge gained using scRNA‐seq in the field of microglia, including novel subpopulations associated with function and development under homeostasis as well during several pathological conditions such as Alzheimer, lipopolysaccharide response, and HIV in relation to the methods employed. Our review points out that despite major developments found using this technique, current scRNA‐seq methods suffer from high cost, low yields, and nonstandardization of generated data. Additional development of scRNA‐seq methods will raise our awareness of microglia's heterogeneity and plasticity under healthy and pathological conditions.

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Drugs Modulating CD4+ T Cells Blood-Brain Barrier Interaction in Alzheimer's Disease

Cited by 12 publications

References 84 publications

Sex differences in the genetic architecture of cognitive resilience to Alzheimer’s disease

Sex differences in the genetic architecture of cognitive resilience to Alzheimer’s disease

Identification of mRNA expression biomarkers associated with epilepsy and response to valproate with co-expression analysis

What has single‐cell RNA sequencing revealed about microglial neuroimmunology?

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