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Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a novel 3D human neuroimmune axis model

ABSTRACT: T cells have been proposed to play a role in Alzheimer’s disease (AD) pathology by infiltrating the brain and interacting with resident cells. Here, we describe a novel three- dimensional (3D) human neuroimmune axis model comprised of human stem cell-derived neurons, astrocytes, and microglia, together with human peripheral immune cells. We used this neuroimmune axis model to examine the infiltration of peripheral immune cells into AD versus control neural-glial cell cultures. Using single-cell RNA- sequencing, we identified that infiltrating T cells into AD cultures led to induction of interferon-gamma and neuroinflammatory-associated pathways in microglial cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239509 | GEO | 2023/08/14

REPOSITORIES: GEO

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The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota

Project description:The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a novel mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide calcitonin gene-related peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+ T lymphocytes induced by skin commensal colonization. Neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology.

2024-02-21 | GSE253063 | GEO

The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota.

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Fully defined human PSC-derived microglia and tri-culture system reveals cell type specific potentiation of complement C3 production in a model of Alzheimer’s disease [smarter-seq]

Project description:Aberrant inflammation in the central nervous system (CNS) has been implicated as a major player in the pathogenesis of human neurodegenerative disease. However, the specific contribution of each cell type to the neuroinflammatory axis in vivo remains unclear with species-specific differences in key signaling pathways further complicating the challenge. To assemble a fully human platform to study neuroinflammation, we first developed a novel approach to derive microglia from human pluripotent stem cells (hPSCs) that faithfully recapitulates microglial ontogeny as validated by single cell RNA-sequencing and stage-specific mapping onto datasets of developing mouse microglia. Using these cells, we build the first defined and completely hPSC-derived tri-culture system containing pure populations of hPSC-derived microglia, astrocytes, and neurons to dissect cellular crosstalk along the neuroinflammatory axis in vitro. We next used the tri-culture system to model neuroinflammation in Alzheimer’s Disease using hPSCs harboring the APPSWE+/+ mutation and their isogenic control. Our data reveal that production of complement C3, a protein that is increased under inflammatory conditions and implicated in synaptic loss, is potentiated under tri-culture conditions, and is further enhanced in APPSWE+/+ tri-cultures. Using cell type-specific ablation studies, we report that C3 potentiation is due to the presence of a neuroinflammatory loop in which microglia are the key initiators that activate reciprocal signaling with astrocytes to produce excess C3. Our study defines the major cellular players contributing to increased C3 in AD and presents a broadly applicable platform to study neuroinflammation in human disease.

2020-11-22 | GSE139549 | GEO

Fully defined human PSC-derived microglia and tri-culture system reveals cell type specific potentiation of complement C3 production in a model of Alzheimer’s disease [scRNA-seq]

2020-11-22 | GSE139550 | GEO

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2020-10-12 | E-MTAB-8059 | biostudies-arrayexpress

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2022-03-24 | GSE199231 | GEO

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2008-03-31 | GSE10238 | GEO

Microbial infection instigates tau-related pathology via activating neuroimmune cGAS-STING pathway

Project description:Microbial infection, the strong trigger to directly induce inflammation in brain, is long considered a risk factor of Alzheimer’s disease, but how these infections contribute to neurodegeneration remains underexplored. Using a modified herpesvirus potentially relevant to this disease, we found that its infection promotes tau-related pathology in part via activating neuroimmune cGAS-STING pathway in the tau mouse models. These represent a causal link of environmental infectious factors and neurodegenerative diseases.

2024-04-11 | GSE229411 | GEO

Gene expression-based, astrocyte treatments

Project description:Astrocytes, a major cell type found throughout the central nervous system have general roles in neuronal development, blood-brain barrier function, regulation of neuroimmune responses as well as metabolic support of other brain resident cells. Here we show that a distinct subtype of reactive astrocyte is induced by activated endothelial cells and is distinct from astrocytes classically activated by neuroinflammatory microglia. We show that activated endothelial cells strongly induce C3 + astrocytes that retain their phagocytic capacity while exhibiting a gain of neurotoxic function decreasing neuronal cell survival. We show that endothelial activated astrocytes have increased A1-astrocytic genes and exhibit a distinctive extracellular matrix remodeling profile. Finally, we show that endothelial activated astrocytes are Decorin positive and are associated to vascular amyloid deposits but not amyloid plaques in mouse models and AD/CAA patients. Taken together these findings show the existence of potentially extensive and subtle functional diversity of A1-reactive astrocytes. Astrocytes treated with Control or Activated Microglia or Endothelial Conditioned media

2022-03-18 | GSE180106 | GEO

Cranial photo-immunologic regulation along the skull-meninges-brain axis for promoting recovery from ischemic brain injury

Project description:Stroke involves in the interaction between central and peripheral immune systems. Skull bone marrows serve as reservoirs for immune cells in brain borders, and can rapidly respond to perturbations in the brain environment. Hence, targeting the skull bone marrow to modulate neuroimmune communications along the calvaria-meninges-brain axis would potentially improve stroke prognosis. Here, we successfully achieved cranial immunomodulation via ultraviolet (UV) irradiation of the interparietal region, which was characterized by rich marrow cavities and channels connecting the skull and meninges. Utilizing the recently-developed long-term clearing cranial window that ensured the integrity of skull, we discovered that the cranial photo-immunologic regulation (CPR) could promote cerebrovascular regeneration and aid in neurovascular repair post ischemic stroke. Single-cell transcriptome analysis revealed that meninge could be a crucial neuroimmune interface for ischemic stroke-induced immune responses. And, CPR could restore the stroke-induced alterations in cellular gene expression, especially meningeal B cells. Further we demonstrated that CPR could effectively alleviate the excessive suppression of meningeal B cell activation caused by ischemic stroke. This work opens avenues for immunoregulation through the skull-meninges-brain axis and provides valuable insights for immunomodulatory therapies in brain diseases.

2024-04-18 | GSE252774 | GEO

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