Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer's disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205569 | GEO | 2023/04/10
REPOSITORIES: GEO
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Project description:Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer's disease
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Project description:This SuperSeries is composed of the SubSeries listed below.
2023-09-28 | GSE227223 | GEO
Project description:In this study, we derived iPS-derived microglia-like cells (iMGLs) from a healthy donor (Sample: Control) CRISPR engineered to carry a dead CAS9 fused to the transcriptional repressor KRAB (dCAS9-KRAB) and treated these cultures with the pro-inflammatory stimulant LPS (Sample: LPS).
2023-09-28 | GSE227222 | GEO
Project description:In this study, we derived iPS-derived microglia-like cells (iMGLs) from a healthy donor (Sample: Control) CRISPR engineered to carry a dead CAS9 fused to the transcriptional repressor KRAB (dCAS9-KRAB) and treated these cultures with pre-formed amyloid beta 1-42 fibrils. We then performed gene expression profiling analysis using data obtained from RNA-seq of treated and untreated cells at 4 different time points.
2023-09-28 | GSE227221 | GEO
Project description:FLT3-ITD+ acute myeloid leukemia (AML) accounts for ?25% of all AML cases and is a subtype that carries a poor prognosis. microRNA-155 (miR-155) is specifically overexpressed in FLT3-ITD+ AML compared with FLT3 wild-type (FLT3-WT) AML and is critical for the growth of FLT3-ITD+ AML cells in vitro. However, miR-155's role in regulating FLT3-ITD-mediated disease in vivo remains unclear. In this study, we used a genetic mouse model to determine whether miR-155 influences the development of FLT3-ITD-induced myeloproliferative disease. Results indicate that miR-155 promotes FLT3-ITD-induced myeloid expansion in the bone marrow, spleen, and peripheral blood. Mechanistically, miR-155 increases proliferation of the hematopoietic stem and progenitor cell compartments by reducing the growth-inhibitory effects of the interferon (IFN) response, and this involves targeting of Cebpb. Consistent with our observations in mice, primary FLT3-ITD+ AML clinical samples have significantly higher miR-155 levels and a lower IFN response compared with FLT3-WT AML samples. Further, inhibition of miR-155 in FLT3-ITD+ AML cell lines using CRISPR/Cas9, or primary FLT3-ITD+ AML samples using locked nucleic acid antisense inhibitors, results in an elevated IFN response and reduces colony formation. Altogether, our data reveal that miR-155 collaborates with FLT3-ITD to promote myeloid cell expansion in vivo and that this involves a multitarget mechanism that includes repression of IFN signaling.
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Project description:Human Microglial State Dynamics in Alzheimer's Disease Progression
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Project description:Gamma oscillations (20-50Hz) are a common local field potential signature in many brain regions that are generated by a resonant circuit between fast-spiking parvalbumin (PV)-positive interneurons and pyramidal cells. Changes in the magnitude and frequency of gamma have been observed in several neuropsychiatric disorders. However, it is unclear how disruptions in gamma oscillations affect cellular pathologies seen in these disorders. Here, we investigate this using the 5XFAD mouse model of Alzheimer’s disease (AD) and find reduced power and magnitude of behaviorally driven gamma oscillatory activity — even before the onset of plaque formation or measurable cognitive decline. Because of the early onset, we aimed to determine if exogenous manipulations of gamma could influence the progression of disease pathology. We find that driving PV-positive neurons at gamma frequency (40Hz) using channelrhodopsin-2 reduced total levels of amyloid-β (Aβ) 40 and 42 isoforms in the hippocampus of 5XFAD mouse. Driving PV-positive neurons at other frequencies, or driving excitatory neurons, did not reduce Aβ levels. Furthermore, driving PV-positive neurons reduced enlarged endosomes in hippocampal neurons and cleavage intermediates of APP in 5XFAD mouse. Gene expression profiling revealed a neuroprotective response with morphological transformation of microglia and markedly increased phagocytosis of Aβ by microglia. Inspired by these observations, we designed a non-invasive light-flickering paradigm that drives 40Hz gamma activity in mouse visual cortex. The light-flickering paradigm profoundly reduced Aβ40 and Aβ42 levels in the visual cortex of pre-symptomatic mice and greatly mitigated plaque load in the visual cortex of aged, symptomatic mice. This reduction was completely blocked by a GABA-A antagonist, providing further support for an essential role of GABAergic signaling in mediating neuroprotective gamma activity. Overall, our findings uncover a dramatic and previously unappreciated function of the brain’s endogenous gamma rhythms in reducing the production and increasing the clearance of Aβ peptides, whose accumulation is believed to drive the pathogenesis of AD.
2016-12-07 | GSE77471 | GEO
Project description:Interferons play a major role in microglial-mediated neuroinflammation in Alzheimer's disease (AD). We investigated the interferon transcriptome (AD versus non-AD) using N9 and murine microglia. We identified 64 interferon-related differentially expressed genes (DEG) in LPS-stimulated N9 microglia versus control cells, 26 DEG in microglia from 5XFAD versus wild-type mice, with 13 DEG common to both datasets. Network analyses identified potential key mediators (Cxcl10, Ifit3) of the interferon response in AD. Gene-drug interaction analysis identified therapeutics targeting interferon-related genes. These data characterize the microglial interferon response in AD, providing new targets and therapeutics directed towards interferon-related neuroinflammation in AD.
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Project description:Alzheimer's disease (AD) is characterized by progressive neurodegeneration associated with the aggregation and deposition of ?-amyloid (A?(40) and A?(42) ) peptide in senile plaques. Recent studies suggest that copper may play an important role in AD pathology. Copper concentrations are elevated in amyloid plaques and copper binds with high affinity to the A? peptide and promotes A? oligomerization and neurotoxicity. Despite this connection between copper and AD, it is unknown whether the expression of proteins involved in regulating copper homeostasis is altered in this disorder. In this study, we demonstrate that the copper transporting P-type ATPase, ATP7A, is highly expressed in activated microglial cells that are specifically clustered around amyloid plaques in the TgCRND8 mouse model of AD. Using a cultured microglial cell line, ATP7A expression was found to be increased by the pro-inflammatory cytokine interferon-gamma, but not by TNF-? or IL-1?. Interferon-gamma also elicited marked changes in copper homeostasis, including copper-dependent trafficking of ATP7A from the Golgi to cytoplasmic vesicles, increased copper uptake and elevated expression of the CTR1 copper importer. These findings suggest that pro-inflammatory conditions associated with AD cause marked changes in microglial copper trafficking, which may underlie the changes in copper homeostasis in AD. It is concluded that copper sequestration by microglia may provide a neuroprotective mechanism in AD.
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Project description:BACKGROUND:Recent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset Alzheimer's disease (LOAD). Amongst these, a polymorphism in phospholipase C-gamma 2 (PLCG2) P522R has been reported to be protective against LOAD. PLC enzymes are key elements in signal transmission networks and are potentially druggable targets. PLCG2 is highly expressed in the hematopoietic system. Hypermorphic mutations in PLCG2 in humans have been reported to cause autoinflammation and immune disorders, suggesting a key role for this enzyme in the regulation of immune cell function. METHODS:We assessed PLCG2 distribution in human and mouse brain tissue via immunohistochemistry and in situ hybridization. We transfected heterologous cell systems (COS7 and HEK293T cells) to determine the effect of the P522R AD-associated variant on enzymatic function using various orthogonal assays, including a radioactive assay, IP-One ELISA, and calcium assays. RESULTS:PLCG2 expression is restricted primarily to microglia and granule cells of the dentate gyrus. Plcg2 mRNA is maintained in plaque-associated microglia in the cerebral tissue of an AD mouse model. Functional analysis of the p.P522R variant demonstrated a small hypermorphic effect of the mutation on enzyme function. CONCLUSIONS:The PLCG2 P522R variant is protective against AD. We show that PLCG2 is expressed in brain microglia, and the p.P522R polymorphism weakly increases enzyme function. These data suggest that activation of PLCγ2 and not inhibition could be therapeutically beneficial in AD. PLCγ2 is therefore a potential target for modulating microglia function in AD, and a small molecule drug that weakly activates PLCγ2 may be one potential therapeutic approach.
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