The neuroinflammatory interleukin-12 signaling pathway drives Alzheimer's disease-like pathology by perturbing oligodendrocyte survival and neuronal homeostasis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE173242 | GEO | 2024/12/31
REPOSITORIES: GEO
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Project description:The neuroinflammatory interleukin-12 signaling pathway drives Alzheimer's disease-like pathology by perturbing oligodendrocyte survival and neuronal homeostasis
| PRJNA724867 | ENA
Project description:Alzheimerâs disease (AD) is a neurodegenerative disease characterized by a marked decline in cognition and memory formation. Increasing evidence highlights the essential role of neuroinflammatory and immune-related molecules, namely the ones that are produced at the brain barriers, on brain immune surveillance, cellular dysfunction and amyloid beta (Aβ) pathology in AD. Therefore, understanding the response at the brain barriers may unravel novel pathways that are relevant for the pathophysiology of AD. Herein, we focused on the study of the choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, in aging and in AD. Specifically, we used the PDGFB-APPSwInd (J20) transgenic mouse model of AD, which presents early memory decline and progressive Aβ accumulation, and littermate age-matched wild-type (WT) mice, to characterize the CP transcriptome at 3, 5-6 and 11-12 months of age. The most striking observation was that the CP of J20 mice displayed an overall overexpression of type I interferon (IFN) response genes at all ages. Moreover, J20 mice presented a high expression of type II IFN genes in the CP at 3 months, which became lower than WT at 5-6 and 11-12 months. Importantly, along with a marked memory impairment and increased glial activation, J20 mice also presented a similar overexpression of type I IFN genes in the dorsal hippocampus at 3 months. Altogether, these findings provide new insights on a possible interplay between type I and type II IFN responses in AD and point to IFNs as mediators of cognitive decline in aging and in AD. The CP transcriptome of at least 3 mice of each age (3, 5-6 and 11-12 months) and of each genotype (WT or J20) was analyzed and compared.
2015-12-31 | E-GEOD-66598 | biostudies-arrayexpress
Project description:Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a marked decline in cognition and memory formation. Increasing evidence highlights the essential role of neuroinflammatory and immune-related molecules, namely the ones that are produced at the brain barriers, on brain immune surveillance, cellular dysfunction and amyloid beta (Aβ) pathology in AD. Therefore, understanding the response at the brain barriers may unravel novel pathways that are relevant for the pathophysiology of AD. Herein, we focused on the study of the choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, in aging and in AD. Specifically, we used the PDGFB-APPSwInd (J20) transgenic mouse model of AD, which presents early memory decline and progressive Aβ accumulation, and littermate age-matched wild-type (WT) mice, to characterize the CP transcriptome at 3, 5-6 and 11-12 months of age. The most striking observation was that the CP of J20 mice displayed an overall overexpression of type I interferon (IFN) response genes at all ages. Moreover, J20 mice presented a high expression of type II IFN genes in the CP at 3 months, which became lower than WT at 5-6 and 11-12 months. Importantly, along with a marked memory impairment and increased glial activation, J20 mice also presented a similar overexpression of type I IFN genes in the dorsal hippocampus at 3 months. Altogether, these findings provide new insights on a possible interplay between type I and type II IFN responses in AD and point to IFNs as mediators of cognitive decline in aging and in AD.
2015-12-31 | GSE66598 | GEO
Project description:We stimulated T-cell blasts from IL23R R381Q homozygotes (n = 2), healthy controls homozygous for the ancestral allele (n = 9), homozygous individuals for TYK2 P1104A (n = 2) that selectively impairs responses to IL-23, and one patient each with autosomal recessive, complete TYK2 or IL-12Rb1 deficiency with IL-12, IL-23, IL-1b, and IL-1b plus IL-23 for 6 hours and performed RNA-sequencing. We used IL-1b as an IL-23-sensitizing agent as previously reported. We found that while T-cell blasts from IL23R R381Q homozygotes respond normally to IL-12 and IL-1b, their response to IL-23 and to IL-23 plus IL-1b is impaired
2023-01-13 | GSE216458 | GEO
Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.
2018-09-18 | PXD009137 | Pride
Project description:Single-cell RNA-sequencing of in vitro differentiated T cells cultured with IL-12+IL-21+IL-23 (Th1 cell condition) or IL-1b+IL-6+IL-23 (pathogenic Th17 cell condition)
2021-05-01 | GSE164518 | GEO
Project description:APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD) with increased odds ratios in females. Targeting amyloid plaques show modest improvement in male non-APOE4 carriers. Leveraging single cell transcriptomics across APOE variants in both sexes, multiplex flow cytometry and validation in two independent cohorts of APOE4 female AD patients, we identify a new subset of neutrophils, interacting with microglia associated with cognitive impairment. This phenotype is defined by increased IL-17 and IL-1 co-expressed gene modules in blood neutrophils and in microglia of cognitively impaired female APOE e4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17+ neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFb, and immune checkpoints including LAG-3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored microglial response to neurodegeneration (MGnD), limiting plaque pathology in AD mice. Mechanistically, IL-17F upregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of MGnD phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE e4 female carriers with cognitive impairment.
2024-06-04 | GSE262632 | GEO
Project description:APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD), with increased odds ratios in females. Targeting amyloid plaques shows modest improvement in male non-APOE4 carriers. Leveraging single-cell transcriptomics across APOE variants in both sexes, multiplex flow cytometry, and validation in two independent cohorts of APOE4 female AD patients, we identify a new subset of neutrophils interacting with microglia associated with cognitive impairment. This phenotype is defined by increased IL-17 and IL-1 co-expressed gene modules in blood neutrophils and in microglia of cognitively impaired female APOE e4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17+ neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFB and immune checkpoints, including LAG-3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored the microglial response to neurodegeneration (MGnD), limiting plaque pathology in AD mice. Mechanistically, IL-17F upregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of MGnD phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE e4 female carriers with cognitive impairment.
2024-06-04 | GSE260461 | GEO
Project description:An adaptive immunological component to neuroinflammatory diseases is increasingly being recognized. The recent identification and characterization of a small population of regulatory T cells (Tregs) resident in the brain allows for the potential therapeutic exploitation. As the most potent known anti-inflammatory mediators, Tregs have the capacity to reduce inflammation and promote tissue repair, with a key limitation being the small number present in brain tissue. Here we demonstrate that transgenic ‘micro-dosing’ of IL-2 production to the brain allows the efficient expansion of the brain-resident Treg population. This approach, using expression of IL-2 within the normal physiological range but redirected to the brain, allows a 10-fold accumulation of Treg numbers within the brain without any increase in the Treg numbers in circulating or peripheral tissues. No alteration was observed in the frequency or transcriptional profile of non-Treg populations within the brain, and, apart from the numerical expansion, brain-resident Tregs were unaltered in their transcriptional profile. Mice with expanded brain-resident Treg numbers were protected from neuroinflammation and damage in mouse models of traumatic brain injury, stroke and Multiple Sclerosis, with substantial reductions in inflammation and histological damage, and improvements in clinical measurements. To produce a treatment with translational potential, we engineered a viral vector delivery system, capable of specific production of IL-2 in the brain. This treatment approach provided a titratable expansion of brain Tregs, and effective protection against neuroinflammatory disease, with potential translation to the patient context.
2022-06-10 | GSE156935 | GEO
Project description:RNA-sequencing of in vitro differentiated T cells cultured with varying cytokine conditions: IL-12, IL-12+IL-21, IL-1b+IL-6+IL-23, and TGFb+IL-6
2022-05-11 | GSE202632 | GEO